N-(1H-indole-4-yl)-benzamides

ABSTRACT

Novel indole carboxamides of the formula ##STR1## wherein R and R 1  are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms and aralkyl of 7 to 12 carbon atoms optionally substituted with 1 to 3 members of the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, --CF 3 , CH 3  S--, --NH 2  and --NO 2  or R 1  and R taken together with the nitrogen atom form an optionally unsaturated heterocycle optionally containing a member of the group consisting of --O--, --S-- and ##STR2## R&#39; is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, phenyl, naphthyl, aralkyl of 7 to 12 carbon atoms and substituted phenyl, R 3  is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3 carbon atoms, chlorine, bromine, iodine, --NO 2 , --NH 2 , acylamide of an aliphatic carboxylic acid of 2 to 5 carbon atoms and mono and dialkylamino with alkyl of 1 to 5 carbon atoms, a and b form ═O and c is hydrogen or a and c form a carbon-carbon bond and b is hydrogen, A is selected from the group consisting of --(CH 2 ) n  -- and ##STR3## n is an integer from 2 to 5, m is an integer from 1 to 3, B is ##STR4## R 2  is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having remarkable anti-arrhytmic properties.

PRIOR APPLICATION

This application is a continuation-in-part of copending U.S. patentapplication Ser. No. 883,915 filed July 10, 1986, now U.S. Pat. No.4,791,109.

STATE OF THE ART

Related indoles are described in copending U.S. patent application Ser.No. 498,835 filed May 27, 1983, Ser. No. 853,030 filed Apr. 17, 1986,and Ser. No. 691,163 filed Jan. 14, 1985 and U.S. Pat. No. 4,333,951 andEuropean Patent No. 89,426.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novelindole-carboxamides of formula I and their non-toxic, pharmaceuticallyacceptable acid addition salts and a novel process for theirpreparation.

It is another object of the invention to provide anti-arrythmiccompositions and to a novel method of inducing anti-arrythmic activityin warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of indole-carboxamides of the formula ##STR5## wherein R andR₁ are individually selected from the group consisting of hydrogen,alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkylalkyl of 4 to 7 carbon atoms and aralkyl of 7 to 12 carbonatoms optionally substituted with 1 to 3 members of the group consistingof halogen, methyl, ethyl, methoxy, ethoxy, --CF₃, CH₃ S--, --NH₂ and--NO₂ or R₁ and R taken together with the nitrogen atom form anoptionally unsaturated heterocycle optionally containing a member of thegroup consisting of --O--, --S-- and ##STR6## R' is selected from thegroup consisting of hydrogen, alkyl of 1 to 5 carbon atoms, phenyl,naphthyl, aralkyl of 7 to 12 carbon atoms and substituted phenyl, R₃ isselected from the group consisting of hydrogen, alkyl of 1 to 5 carbonatoms, alkoxy of 1 to 3 carbon atoms, chlorine, bromine, iodine, --NO₂,--NH₂, acylamide of an aliphatic carboxylic acid of 2 to 5 carbon atomsand mono and dialkylamino with alkyl of 1 to 5 carbon atoms, a and bform ═O and c is hydrogen or a and c form a carbon-carbon bond and b ishydrogen, A is selected from the group consisting of --(CH₂)_(n) -- and##STR7## n is an integer from 2 to 5, m is an integer from 1 to 3, B is##STR8## R₂ is selected from the group consisting of hydrogen and alkylof 1 to 5 carbon atoms and their non-toxic, pharmaceutically acceptableacid addition salts.

In the compounds of formula I, examples of linear and branched alkyl aremethyl, ethyl, propyl, isopropyl and tert.-butyl. Examples of cycloalkylof 3 to 7 carbon atoms are cyclopropyl, cyclobutyl, cyclohexyl andpreferably cyclopentyl; examples of cycloalkylalkyl are cyclobutylmethyland preferably cyclopropylmethyl. Examples of aralkyl of 7 to 12 carbonatoms are benzyl and phenethyl optionally substituted with 1 to 3members of the group consisting of halogen, methyl, ethyl, methoxy,ethoxy, CF₃ --, CH₃ S--, --NH₂ and --NO₂. Examples of heterocyclesformed by R and R₁ with the nitrogen atom to which they are attached arepyrrolidino, piperidino, morpholino, piperazinyl, methylpiperazinyl,ethylpiperazinyl and propylpiperazinyl. The substituted phenyl may besubstituted with the same substituents as benzyl and phenethyl above.

Examples of alkoxy of 1 to 3 carbon atoms are methoxy, ethoxy, propoxyand isopropoxy and examples of aliphatic acyls of 2 to 5 carbon atomsare acetyl and propionyl.

Examples of suitable acids for the formation of the non-toxic,pharmaceutically acceptable acid addition salts are inorganic acids suchas hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid andphosphoric acid and organic acids such as formic acid, acetic acid,propionic acid, maleic acid, fumaric acid, succinic acid, tartaric acid,citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkane sulfonicacids such as methane sulfonic acid and ethane sulfonic acid,arylsulfonic acids such as benzene sulfonic acid or p-toluene sulfonicacid and arylcarboxylic acids such as benzoic acid.

Among the preferred compounds of formula I are those wherein R₂ ishydrogen, those wherein a and c form a double bond and those wherein R₃is hydrogen, those wherein ##STR9## is in the ortho position and thosewherein B is ##STR10## with the --NH-- next to the indole side andnon-toxic, pharmaceutically acceptable acid addition salts.

In the compounds of formula I', the alkyl is preferably methyl, ethyl,n-propyl, isopropyl or tert.-butyl and the alkoxy is preferably methoxy,ethoxy or n-propoxy. In the alkylamino or dialkylamino moieties, thealkyls are preferably methyl or ethyl.

When X, X₁, X₂, X₃, X₄, X₅ and X₆ are halogen, they are preferablychlorine, but they can also be fluorine, bromine or iodine. Thealiphatic acyl of 2 to 5 carbon atoms preferably is acetyl or propionyl.The alkenyl and alkynyl of 3 to 5 carbon atoms preferably is allyl orpropargyl.

Other preferred compounds of the invention are those of the formula##STR11## wherein either R₂ and R₃ are both hydrogen, B is --CONH--, NHbeing on the indole side, b is hydrogen, a and c together form a secondbond between the carbons which bear them, A is ##STR12## and either R₁is hydrogen and R is selected from the group consisting of1,1-dimethylpropyl, ##STR13## R and R₁ together form with the nitrogenatom to which they are attached morpholino or R₂ and R₃ are bothhydrogen, B is --CO--NH--, NH being on the indole side, b is hydrogenand a and c together form a second bond between the carbons which bearthem, A is --(CH₂)₃ --, R₁ is hydrogen and R is selected from the groupconsisting of 1,1-dimethylpropyl, cyclohexyl, cyclohexylmethyl, propyl,isopropyl and ##STR14## or R₂ and R₃ are both hydrogen, B is NH--CO,##STR15## being on the indole side, b is hydrogen and a and c togetherform a second bond between the carbons which bear them, A is --(CH₂)₃--, R₁ is hydrogen and R is selected from the group consisting ofcyclopentyl, cyclohexyl, 1,1-dimethylpropyl and ##STR16## or R₂ and R₃are hydrogen, B is --NH--CO--, --NH being on the indole side, b ishydrogen and a and c together form a second bond between the carbonswhich bear them, A is --(CH₂)₄ --, R₁ is hydrogen and R is1,1-dimethylethyl or R₂ is methyl and R₃ is hydrogen, B is --NH--CO--,NH being on the indole side, b is hydrogen and a and c together form asecond bond between the carbons which bear them, A is ##STR17## and R is1,1-dimethylethyl, or R₁ and R form, with the nitrogen atom to whichthey are attached ##STR18## in which Z is ##STR19## n₁ is 1, 2 or 3 andX, X₁, X₂, X₃, X₄, X₅ and X₆ are individually selected from the groupconsisting of hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3carbon atoms, halogen, nitro, amino, monoalkylamino or dialkylaminoradical, with the proviso that X, X₁ and X₂ are not all three hydrogen,A is --(CH₂)_(n) -- n is 2, 3, 4 or 5 or ##STR20## in which m is 1, 2 or3, B is --CO--NH-- or --NH--CO--, R₃ is hydrogen, alkali of 1 to 5carbon atoms, alkoxy of 1 to 3 carbon atoms, chlorine, bromine oriodine, nitro or amino optionally substituted with an aliphatic acyl of2 to 5 carbon atoms or with alkyl of 1 to 5 carbon atoms, a togetherwith b is an oxo group, or together with c is a second bond between thecarbons which bear them, b is hydrogen or together with a oxo, c ishydrogen or together with a is a second bond between the carbons whichbear them, and R₂ is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl oralkynyl of 2 to 5 carbon atoms or aralkyl of 7 to 12 carbon atomsoptionally substituted with 1, 2 or 3 members of the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio,amino and nitro or cycloalkylalkyl of 4 to 7 carbon atoms.

The cycloalkylalkyl of 4 to 7 carbon atoms preferably iscyclopropylmethyl or cyclobutylmethyl. The aralkyl of 7 to 12 carbonatoms preferably is benzyl or phenethyl.

More preferred compounds of formula I' are those wherein R₁ and Rtogether with the nitrogen form ##STR21## in which Z has the abovemeaning, A is ##STR22## or --(CH₂)₃ -- or --(CH₂)₄ --, R₃ is hydrogen,R₂ is hydrogen or methyl, b is hydrogen and a and c together form asecond bond between the carbons which bear them.

Another preferred group of compounds having particularly interestinganti-arythmic activity are compounds of the formula, ##STR23## whereinone of X or Y is selected from the group consisting of alkyl of 1 to 5carbon atoms, alkoxy of 1 to 3 carbon atoms, chlorine, bromine, iodine,--NO₂, amino optionally substituted with acyl of 2 to 5 carbon atoms orone or two alkyls of 1 to 5 carbon atoms and the other is hydrogen withthe proviso that Y is not methoxy when X is chlorine and theirnon-toxic, pharmaceutically acceptable acid addition salts.

Among preferred compounds of formula I" are those wherein Y is hydrogenand X is methoxy, --NH₂, amino or acetylamino and those wherein X ishydrogen and Y is chlorine, nitro, amino and acetylamino and theirnon-toxic, pharmaceutically acceptable acid addition salts.

Examples of specific preferred compounds of formula I are

2-[-[(1,1-dimethylethyl)amino]ethoxy]-N-(1H-indol-4-yl)benzamide,

2-[-[(1,1-dimethylethyl)amino]-2-hydroxypropoxyl-N-(1H-indol-4-yl)benzamide

2-[3-[[bis-(1-methylethyl]amino]-2-hydroxypropoxyl]-N-(1H-indol-4-yl)benzamide,and

2-[3-[(1,1-dimethylethyl)amino]propoxy]-N-(1H-indol-4-yl)benzamide,

2-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideand its benzoate and its neutral oxalate,

2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1-methyl-1H-indol-4-yl)benzamideand its hydrochloride,

2-[2-hydroxy-3-[(1,1,3,3-tetramethylbutyl)amino]propoxy)-N-(1H-indol-4-yl)benzamide,

2-[2-hydroxy-3[4-(diphenylmethyl)-1-piperazinyl]-propoxy)-N-(1H-indol-4-yl)benzamideand its neutral oxalate and2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-5-nitro-benzamideand their non-toxic, pharmaceutically acceptable acid addition salts.

The novel process of the invention for the preparation of the compoundsof formula I comprises reacting a compound of the formula ##STR24##wherein B, R₂ and R₃ have the above definitions with a halide of theformula

    G--Hal                                                     III

wherein Hal is chlorine, bromine or iodine and G is selected from thegroup consisting of --(CH₂)_(n) --D and ##STR25## wherein n and m havethe above definitions and D is selected from the group consisting ofchlorine, bromine, iodine, --OH and and a sulfonate of --OH to obtain acompound of the formula ##STR26## wherein B, R₂ and R₃ have the abovedefinitions and G' is selected from the group consisting of --(CH₂)_(n)--Hal and ##STR27## reacting the latter with an amine of the formula##STR28## wherein R and R₁ have the above definitions to obtain acompound of the formula ##STR29## wherein A, B, R, R₁, R₂ and R₃ havethe above definitions which may be isolated and/or salified or when oneof R and R₁ is hydrogen, the latter is subjected to an alkylationreaction or reacted with a halogenating agent to obtain a compound ofthe formula ##STR30## wherein Hal₁ is a bromine or chlorine and A, B, R,R₁, R₂ and R₃ have the above definitions and subjecting the latter tohydrolysis to obtain a compound of the formula ##STR31## wherein A, B,R, R₁, R₂ and R₃ have the above definitions which is isolated and, ifdesired, salified.

When A is a chain of the formula --(CH₂)_(n) --, a halide of formula IIIof the formula:

    Hal--(CH.sub.2).sub.n --D

is used wherein D is chlorine, bromine or iodine and Hal has the abovesignificance. It is preferable that D and Hal should be two differenthalogens to avoid the condensation of two molecules of the compound offormula IV. Accordingly, for example, when D is a chlorine atom, a morereactive halide such as the bromide will be chosen for Hal.

When a hydroxylated halide of formula III has the formula

    HO--(CH.sub.2).sub.n --Hal

in which n and Hal have the above definitions, it is preferred tooperate in the presence of triphenyl phosphine and ethylazodicarboxylate in tetrahydrofuran.

Advantageously, a sulfonate of this hydroxylated derivative is used,preferably, its tosylate of the formula

    TsO--(CH.sub.2).sub.n --Hal

wherein Ts represents a tosyl radical (4-methylbenzene sulfonate) and nand Hal have the above definitions. The operation is then done by phasetransfer, using preferably as the aqueous phase an aqueous solution ofan alkaline hydroxide such as potassium hydroxide or sodium hydroxideand as the organic phase non-miscible with water a solvent such asbenzene in the presence of a transfer agent such as a quaternaryammonium salt of tetrabutyl ammonium, particularly the bromide or thehydrogenosulfate.

The reaction of the product of formula IV with the amine of formula V iscarried out, for example, in an inert organic solvent such as dioxane,benzene, toluene, dimethylformide, or even an alcohol, preferablyethanol, preferably in the presence of a condensation agent such as analkali metal carbonate or bicarbonate like potassium carbonate, analkali metal hydroxide like sodium hydroxide or potassium hydroxide, ora tertiary amine such as triethylamine. The operation can also be doneutilizing directly the amine of formula V as solvent.

When A is ##STR32## a halide is used of the formula ##STR33## and inthis case, Hal is preferably chlorine. The reaction of the derivative offormula II with the halide of formula III is then preferably carried outin the presence of a base such as potassium carbonate or sodiumcarbonate or sodium hydroxide or potassium hydroxide.

The reaction of the compound of formula IV in which G' is ##STR34## withthe amine of formula V is carried out either directly using the amine assolvent, or by using a solvent such as an aliphatic alcohol likemethanol or ethanol.

In the product of formula I_(A), the possible alkylation of thesecondary amine of the lateral chain is carried out by the action of analkyl halide in the presence of an alkali metal carbonate such as sodiumor potassium carbonate in an organic solvent. When it is desired tocarry out a methylation, it is preferred to use formaldehyde in thepresence of a reducing agent such as sodium cyanoborohydride in asolvent such as an aliphatic alcohol such as methanol. Methyl p-toluenesulfonate can also be made to react in the presence of an alkali metalcarbonate such as potassium or sodium carbonate in an organic solventsuch as xylene.

The halogenation of the derivatives of formulae I_(A) can be carriedout, for example with the brominated complex of pyridine of the formula##STR35## Br₂, HBr in the case of bromination. It is advantageouslycarried out with a N-halo-succinimide, preferably the N-bromo or theN-chlorosuccinimide: the operation is done in dioxane or preferably inacetic acid. The product of formula VI obtained is preferably achlorinated product.

The hydrolysis of the product of formula VI is carried out, preferably,with a mineral acid such as phosphoric acid, sulfuric acid, orpreferably hydrochloric acid in aqueous solution. This solution can beused concentrated, but is preferably diluted, for example in normalsolution. There can also be used a solvent such as an aliphatic alcohollike ethanol.

The compounds of formula II can be prepared as follows: To obtain aderivative of formula II_(a) ##STR36## wherein R₂ and R₃ have the abovedefinition, the corresponding methyl or ethyl indol-4-carboxylate or thecorresponding indol-4-carboxylic acid is reacted witha derivative ofaminophenol of the formula ##STR37## wherein K is hydrogen atom or aprotective group of the hydroxy to obtain a compound of the formula##STR38## wherein K and R₂ have the above definition wherein ifnecessary, the hydroxy function is freed to obtain the product offormula II_(A).

By protective group K of the hydroxy, a benzyl or a tosyl is intended,for example, but preferably tosyl. The reaction of methyl or ethyl indol4-carboxylate with the derivative of formula VII is preferably carriedout in the presence of triisobutylaluminum. The solvent utilized ispreferably chloroform and the operation is advantageously carried out atreflux of the reaction mixture.

The reaction of indol-4-carboxylic acid with the derivative of formulaVII is carried out in the presence of a dehydrating agent such ascarbonyldiimidazole or preferably dicyclohexylcarbodiimide in a solventsuch as tetrahydrofuran. The deblocking of the hydroxy of the compoundof formula VIII is carried out by hydrogenolysis when K is benzyl, or bysaponification when K is tosyl, preferably by means of sodium orpotassium hydroxide in a solvent such as a low molecular weight alkanolsuch as methanol or preferably ethanol.

To obtain a derivative of the formula ##STR39## wherein R₂ and R₃ havethe above definitions, the corresponding 4-amino-indole is reacted witha methyl or ethyl carboxylate of the phenol or with hydroxy-benzoic acidto obtain the compound of formula II_(B). When a methyl or ethylcarboxylate of phenol is used, the operation is preferably done in thepresence of triisobutylaluminum in a solvent such as chloroform and isdone advantageously at reflux of the reaction mixture. When a methyl orethyl carboxylate of phenol is used, the operation is done underidentical conditions to those indicated for the preparation of thecompound of formula II_(A) starting with methyl or ethylindole-4-carboxylate. When hydroxy-benzoic acid is used, the operationis done in conditions identical to those indicated for the preparationof the compound of formula II starting with indol-4-carboxylic acid.

In a variation of the process for the preparation of the compounds offormula I wherein A is --(CH₂)_(n) --, a derivative of formula II isreacted with a derivative of the formula ##STR40## wherein Hal, n, R andR₁ have the above definitions to obtain the compound of formula I_(A)which is converted, if desired, into the corresponding product offormula I_(B). The derivative of formula IX is reacted in the form of afree amine or, preferably, in the form of a salt like a hydrochloride.

In another variation of process for the preparation of the compounds offormula I wherein R₃ is an optionally substituted amino radical, thederivative in which R₃ is nitro is reduced and, if desired, the aminoderivative is reacted with a reactive derivative of the substituentwhich is intended to be introduced. The corresponding conditions ofcarrying out are known to one skilled in the art.

The compounds of formula I have a basic character and the addition saltsof the compounds of formula I ca be pdepared advantageously by reactinga mineral or organic acid in esentially stoichiometric proportions withthe said derivative of formula I. The salts can be prepared withoutisolating the corresponding bases.

The novel anti-arrythmic compositions of the invention are comprised ofan anti-arrythmically effective amount of at least one compound offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and an inert pharmaceutical carrier or excipient. The compositionsmay be in the form of tablets, dragees, gelules, capsules, granules,suppositories and injectable solutions or suspensions.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles,fatty bodies of animal or vegetable origin, paraffinic derivatives,glycols, diverse wetting agents, dispersants and emulsifiers andpreservatives.

The compositions are useful for the treatment of cardiac insufficiency,all forms of angor and for the treatment of arrythmia.

Among the preferred compositions of the invention are those wherein inthe active compound a and c form a double bond, those wherein in theactive compound R₂ is hydrogen, those wherein R₃ is hydrogen, thosewherein ##STR41## is in the ortho position and those wherein B is##STR42## with the --NH-- next to the indole and their non-toxic,pharmaceutically acceptable acid addition salts. Specific preferredcompositions are those wherein the active ingredient is2-[2-[(1,1-dimethylethyl)amino]ethoxy]-N-(1H-indol-4-yl)benzamide,2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide,2-[3-[[bis-(1-methylethyl]-amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide,2-[3-[(1,1-dimethylethyl)amino]propoxy]-N-(1H-indol-4-yl)benzamide2-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideand its benzoate and its neutral oxalate,2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1-methyl-1H-indol-4-yl)benzamideand its hydrochloride,2-[2-hydroxy-3-[(1,1,3,3-tetramethylbutyl)amino]propoxy]-N-(1H-indol-4-yl)benzamide,2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]-propoxy]-N-(1H-indol-4-yl)benzamideand its neutral oxalate and2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-5-nitro-benzamide and their pharmaceutically acceptable acid additionsalts.

The novel method of the invention for inducing anti-arrythmic activityin warm-blooded animals, including humans, comprises administering towarm-blooded animals an anti-arrythmically effective amount of at leastone compound of formula I and their non-toxic, pharmaceuticallyacceptable acid addition salts. The compounds may be administeredorally, rectally or parenterally and the usual daily dose is 0.65 to13.5 mg/kg of dep-nding on the compound, method of administration andcondition treated. For example, the compound of Example 5 may beadministered orally at a daily dose of 3 to 12 mg/kg in for treatment ofventricular, supra-ventricular and junction arrythmia.

The novel intermediates of the invention have the formula ##STR43## inwhich B, R₂ and R₃ have the above definitions.

In addition to the products described in the examples, the followingproducts constitute new products which are within the scope of thepresent invention:2-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide,2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1-methyl-1H-indol-4-yl)benzamideand 2-[3-(4-morpholinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1N-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxyl]-phenyl]-1H-indol-4-carboxamideand its neutral oxalate Step A:N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide

140 ml of triisobutylaluminum in solution in toluene at 1.1 mole/l wereadded to a solution of 18 g of 2-aminophenol-4-methylbenzenesulfonate in300 ml of chloroform, and after stirring for 15 minutes, a solution of12.15 g of methyl indol-4-carboxylate in 120 ml of chloroform was added.The mixture was refluxed for 20 hours and was then cooled to 0° to -10°C. and 500 ml of an N aqueous solution of hydrochloric acid were addedwith stirring over 15 minutes. The chloroform phase was then purified bychromatography over silica (eluent:methylene chloride) to obtain 25 g ofN-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide meltingat 135° C.

Step B: N-(2-hydroxyphenyl)-1H-indol-4-carboxamide

250 ml of a solution of potassium hydroxide in ethanol at 10 g per 100ml were added to a suspension of 25 g ofN-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide in 50ml of ethanol at 95° C. with stirring under an inert atmosphere and themixture was stirred for 21 hours. 1 liter of iced water was added, andthe mixture was acidified with a concentrated aqueous solution ofhydrochloric acid, followed by stirring for a further 15 minutes,filtering, drying and triturating at reflux in 1.5 liters of methylenechloride. After concentrating to about 300 ml, filtering and drying at80° C. under reduced pressure, 13 g ofN-(2-hydroxyphenyl)-1H-indol-4-carboxamide melting at ≃208° C. wereobtained.

    ______________________________________                                        U.V. Spectrum (ethanol)                                                       ______________________________________                                        Max. at 230 nm  E.sub.1.sup.1 = 1,012                                                                      ε = 25,500                               Infl. at 265 nm E.sub.1.sup.1 = 208                                           Max. at 304 nm  E.sub.1.sup.1 = 564                                                                        ε = 14,200                               Infl. at 318 nm E.sub.1.sup.1 = 482                                           ______________________________________                                    

Step C: N-[2-[(2-oxiranyl)methoxy]phenyl]-1H-indol-4-carboxamide

Under an inert atmosphere, a solution of 3 g ofN-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 1.65 g of potassiumcarbonate in 100 ml of acetone was refluxed for 24 hours with 4.7 ml ofepichlorhydrin and after purifying by chromatography over silica(eluent: ethyl acetate-triethylamine, 9-1) and evaporating to dryness,the residue was triturated in pentane, then filtered and dried underreduced pressure at 60° C. to obtain 2.8 g ofN-[2-[(2-oxiranyl)methoxy]phenyl]-1H-indol-4-carboxamide melting at 122°C.

Step D:N-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]-1H-indol-4-carboxamide

A solution of 2.8 g of the product from Step C for 1 hour in 40 ml ofethanol and 7.6 ml of tert-butylamine was heated at 80° C. under aninert atmosphere with stirring and after purification by chromatographyover silica (eluent: ethyl acetate-triethylamine, 9-1, thenchloroform-methanol 5-5), 3.05 g ofN-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl-1-indol-4-carboxamidewere obtained (amorphous beige-colored powder).

2.9 g of said product dissolved in 300 ml of acetone was admixed with480 mg of oxalic acid and the mixture was refluxed for 15 minutes. Afterconcentration to about 200 ml, cooling, filtering and drying underreduced pressure at 80° C., 2.9 g of the oxalate product were obtained,and 2.35 g after crystallization from methanol melted at ≃200° C.

EXAMPLE 2N-[2-[2-[(1,1-dimethylethylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamideand its hydrochloride Step A:N-[2-(2-chloroethoxy)phenyl]-1H-indol-4-carboxamide

2.5 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 100 ml of benzeneand 50 ml of acetonitrile with 850 mg of n-tetra-butylammoniumhydrogensulfate, 3.6 ml of 3-chloroethyl p-toluene sulfonate and 50 mlof 5N sodium hydroxide were heated with stirring at 60° C. under aninert atmosphere. After cooling and decanting and extraction with ethylacetate, the extracts were purified by chromatography over silica(eluent: dichloroethane). Evaporation to dryness under reduced pressureat 50° C. yielded 1.65 g of N-[2-(2-chloroethoxy)phenyl]-1H-indol-4-carboxamide melting at ≃135° C.

Step B:N-[2-[2-[(1,1-dimethylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamide

With stirring at a pressure of 2 bars, a solution of 2.3 g of theproduct from Step A in 40 ml of ethanol and 37.5 ml of tert-butylaminewas heated at 120° C. for 24 hours. After dilution with 400 ml of waterand 400 ml of ethyl acetate, the solution was alkalized with sodiumhydroxide and saturated with potassium carbonate. The mixture wasextracted with ethyl acetate and the crystals obtained were trituratedwith ether to obtain 2.3 g of N-[2-[2-[(1,1-dimethylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamide melting at ≃148° C.

Formation of the Hydrochloride

The said base was dissolved in 200 ml of ethyl acetate and a solution ofhydrogen chloride in ethyl acetate was added until the pH was acidic.The mixture was refluxed for 15 minutes and after concentrating to about100 ml, cooling, filtering, drying at 80° C. under reduced pressure andcrystallizing from isopropanol, 2.15 g ofN-[2-[2-[(1,1-dimethylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamidehydrochloride melting at ≃260° C. were obtained.

    ______________________________________                                        U.V. Spectrum (ethanol)                                                       ______________________________________                                        Max. at 229 nm  E.sub.1.sup.1 = 724                                                                       ε = 28,100                                Max. at 302 nm  E.sub.1.sup.1 = 303                                                                       ε = 11.750                                ______________________________________                                    

EXAMPLE 3N-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]-1H-indol-4-carboxamidehydrochloride Step A:N-[2-(3-chloropropoxy)phenyl]-1H-indol-4-carboxamide

A solution of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide, 150 mlof tetrahydrofuran, 0.65 ml of 3-chloropropanol and 2.1 g oftriphenylphosphine was prepared with stirring under an inert atmosphereand then slowly 1.2 ml of ethyl azodicarboxylate were added. The mixturewas stirred for 3 hours after which 2.1 g of triphenylphosphine and 0.65ml of 3-chloropropanol were added. Then, slowly, 1.2 ml of ethylazodicarboxylate were added and the mixture was stirred for 16 hours.Then the mixture was evaporated to dryness and the residue was purifiedby chromatography over silica (eluent: methylene chloride). The solutionwas evaporated to dryness, triturated with isopropyl ether, filtered anddried under reduced pressure to obtain 1.3 g ofN-[2-(3-chloropropoxy)phenyl]-1H-indol-4-carboxamide melting at ≃144° C.

Step B:N-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]-1H-indol-4-carboxamidehydrochloride

3.1 g of the product of Step A were heated at 100° C. under a pressureof 2 bars with stirring in 60 ml of ethanol and 30 ml of tertbutylamine.After diluting with 200 ml of water, acidifying with a concentratedaqueous solution of hydrochloric acid, filtering and washing with water,then triturating first with ether then with hot acetone for 15 minutesat reflux, 2.9 g ofN-[2-[3-[(1,1-dimethylethyl)amino]propoxy]phenyl]-1H-indol-4-carboxamidehydrochloride melting at ≃238° C. were obtained.

    ______________________________________                                        U.V. Spectrum (ethanol)                                                       ______________________________________                                        Max. at 227 nm  E.sub.1.sup.1 = 709                                                                       ε = 28,400                                Infl. at 262 nm E.sub.1.sup.1 = 130                                           Max. at 301 nm  E.sub.1.sup.1 = 327                                                                       ε = 13,100                                Infl. at 320 nm E.sub.1.sup.1 = 227                                           ______________________________________                                    

EXAMPLE 42-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide and its neutral oxalate Step A:2-[N-(1H-indol-4-yl)amido/phenol

92 ml of a 1.1 mole/oiter solution of triisobutylaluminum in toluenewere added with stirring under an inert atmosphere to a solution of 6.6g of 4-amino indole in 250 ml of chloroform and then 9.6 ml of methylsalicylate were added. The mixture was refluxed for 20 hours and thencooled to ambient temperature. 300 ml of N hydrochloric acid and 300 mlof methylene chloride were added, followed by washing with water, dryingover a desiccant, filtering, evaporating to dryness under reducedpressure at 50° C., triturating with ether, filtering and drying at 60°C. under reduced pressure to obtain 9.4 g of2-[N-(1H-indol-4-yl)amido]phenol melting at ≃232° C.

    ______________________________________                                        U.V. Spectrum (ethanol)                                                       ______________________________________                                        Infl. at 216 nm E.sub.1.sup.1 = 1,595                                         Infl. at 233 nm E.sub.1.sup.1 = 680                                                                        ε = 17,200                               Infl. at 262 nm E.sub.1.sup.1 = 187                                           Infl. at 303 nm E.sub.1.sup.1 = 482                                                                        ε = 12,200                               Infl. at 314 nm E.sub.1.sup.1 = 494                                                                        ε = 12,500                               ______________________________________                                    

Step B:2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide and its neutral oxalate

Using the procedure of example 1, 3.5 g of 2-/N-(1H-indol-4-yl)amido/phenol were reacted to obtain 3 g of the oxalate melting at 190°C.

    ______________________________________                                        U.V. Spectrum (ethanol + HCl 0.1 N)                                           ______________________________________                                        Infl. at 216 nm    E.sub.1.sup.1 = 1,003                                      Max. at 296 nm     E.sub.1.sup.1 = 264                                                                       ε = 11,300                             Infl. at 235, 274, 288, 309 nm                                                ______________________________________                                    

EXAMPLE 52-[2-[1,1-dimethylethyl)amino]ethoxy]-N-(1H-indol-4-yl)-benzamidehydrochloride

Using the procedure of Example 2, 27 g of2-[N-(1H-indol-4-yl)amido]phenolbenzamide were reacted to obtain 4.4 gof 2-[2-[1,1-dimethylethyl)amino]ethoxy]-N-(1H-indol-4-yl)-benzamidehydrochloride melting at ≃248° C.

    ______________________________________                                        U.V. Spectrum (ethanol or ethanol + HCl 0.1 N)                                ______________________________________                                        Infl. at 215 nm E.sub.1.sup.1 = 1,099                                                                      ε = 42,600                               Max. at 293 nm  E.sub.1.sup.1 = 285                                                                        ε = 11,100                               ______________________________________                                    

EXAMPLE 62-[3-[(1,1-dimethylethyl)amino]propoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 3, 5 g of2-[N-(1H-indol-4-yl)amido]-phenol benzamide were reacted to obtain 3.1 gof 2-[3-[(1,1-dimethylethyl)amino]propoxy]-N-(1H-indol-4-yl)benzamidemelting at ≃146° C., then 3.1 g of its oxalate melting at ≃180° C.

    ______________________________________                                        U.V. Spectrum of the oxalate (ethanol)                                        ______________________________________                                        Infl. at 218 nm E.sub.1.sup.1 = 879                                           Max. at 297 nm  E.sub.1.sup.1 = 246                                                                       ε = 11,200                                ______________________________________                                    

EXAMPLE 7 N-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide

3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene,25 ml of acetonitrile and 50 ml of a 5N aqueous solution of sodiumhydroxide were heated to 60° C. for 3 hours with stirring under an inertatmosphere with 0.4 g of 2-tetrabutylammonium hydrogenosulfate and 2.2 gof 2-piperidino-1-chloroethane. After cooling, decanting, extractingwith ethyl acetate and purifying by chromatography over silica (eluent:ethyl acetate-triethylamine, 9-1), 3.6 g ofN-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide wereobtained.

Formation of the Fumarate

The said base was dissolved in 100 ml of isopropanol and 1.15 g offumaric acid were added. The mixture was refluxed and after cooling,filtering, and taking to dryness under reduced pressure, 3.80 g of thefumarate were obtained in two lots melting at ≃186° C. aftercrystallization from ethanol.

    ______________________________________                                        U.V. Spectrum                                                                 ______________________________________                                        Infl. at 230 nm E.sub.1.sup.1 = 681                                           Infl. at 260 nm E.sub.1.sup.1 = 141                                           Max. at 300 nm  E.sub.1.sup.1 = 271                                                                       ε = 13,000                                Infl. at 320 nm E.sub.1.sup.1 = 224                                           ______________________________________                                    

EXAMPLE 8 N-[2-[2-(dimethylamino)ethoxy]phenyl]-1H-indol-4-carboxamide

Using the procedure of Example 7, the hydrochloride ofdimethylaminoethyl chloride was reacted to obtain 3.6 g ofN-[2-[2-(dimethylamino)ethoxy]phenyl]-1H-indol-4-carboxamide melting at110° C. then 4.4 g of tartrate (softening point--110° C.)

    ______________________________________                                        U.V. Spectrum of the tartrate (ethanol)                                       ______________________________________                                        Max. at 228 nm  E.sub.1.sup.1 = 559                                                                       ε = 26,500                                Infl. at 263 nm E.sub.1.sup.1 = 123                                           Max. at 300 nm  E.sub.1.sup.1 = 261                                                                       ε = 12,400                                ______________________________________                                    

EXAMPLE 9N-[2-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamide

Using the procedure of Example 7, 8.5 g of the hydrochloride ofdiisopropylaminoethyl chloride were reacted to obtain 4 g ofN-[2-[2-[bis(1-methylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamidemelting at 145° C. then 2.9 g of the hydrochloride melting at 214° C.

EXAMPLE 10 N-(1H-indol-4-yl)-2-[2-(1-piperidinyl)ethoxy]-benzamide

Using the procedure of Example 7, 2.5 g of 2-[N-(1H-indol-4-yl)_(amido)]phenol and 1.84 g of 2-piperidine-1-chloroethane hydrochloride werereacted to obtain 3.0 g ofN-(1H-indol-4-yl)-2-[2-(1-piperidinyl)ethoxy]-benzamide melting at 154°C. after crystallization from ethyl ether.

Formation of the Phosphate

2.7 g of the said base were dissolved in 500 ml of ethanol and 10 ml ofa 1M solution of phosphoric acid in ethanol were added. The mixture washeated to reflux and 500 ml of methanol were added. The reaction mediumwas filtered hot, partially concentrated and then cooled, filtered anddried under reduced pressure at 80° C. After crystallizing from anethanol-methanol mixture (1-1), 2.4 g of the phosphate product melting238° C. were obtained

    ______________________________________                                        Analysis: C.sub.22 H.sub.25 N.sub.3 O.sub.2.H.sub. 3 PO.sub.4 molecular       weight = 461.458                                                              ______________________________________                                        Calculated                                                                             % C    57.26  % H  6.12 % N  9.11 % P  6.71                          Found           57.1        6.2       9.0       6.6                           ______________________________________                                    

EXAMPLE 11 2-[2-(dimethylamino)ethoxy]-N-(1H-indol-4-yl) benzamide

Using the procedure of Example 7, 2.5 g of2-[N-(1H-indol-4-yl)amido]phenol and 1.44 g of dimethylaminoethylchloride hydrochloride were heated for 24 hours to obtain 2.15 g of basemelting at 138° C. after crystallization from ethyl ether.

Using the procedure of Example 10, 3.3 g of the said base and replacingthe ethanol with isopropanol, 3.5 g of the phosphate product wereobtained.

    ______________________________________                                        Analysis: C.sub.19 H.sub.21 N.sub.3 O.sub.2, H.sub.3 PO.sub.4 : molecular     weight = 421.37                                                               ______________________________________                                        Calculated                                                                             % C    54.15  % H  5.70 % N  9.97 % P  7.35                          Found           53.8        5.8       9.8       7.3                           ______________________________________                                    

EXAMPLE 12 2-[2-[bis(1-methylethyl)-amino]ethoxy-]N-(1H-indol-4-yl)benzamide

Using the procedure of Example 7, 3.5 g of2-[N-(1H-indol-4-yl)amido]phenol and 2.8 g of diisopropylaminoethylchloride hydrochloride were reacted to obtain 5.7 g of crude productwhich was purified by chromatography over silica (eluent:chloroform-acetone-triethylamine, 6-3-1) and crystallizing fromchloroform, then from a mixture of isopropanol and methanol (2-1) toobtain 2.25 g of 2-[2-[bis(1-methylethyl)-amino]ethoxy-N-(1H-indol-4-yl)benzamide melting at 180° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.29 N.sub.3 O.sub.2 : molecular weight                ______________________________________                                        = 379.48                                                                      Calculated                                                                             % C     72.79   % H   7.70  % N   11.07                              Found            72.9          7.9         10.9                               ______________________________________                                    

EXAMPLE 13 2-[2-hydroxy-3-(propylamino)-propoxy]-N-(1H-indol-4-yl)benzamide

3.1 g of 2-[(2-oxiranyl) methoxy]-N-(1H-indol-4-yl) benzamide preparedas in example 4 is heated for 2 hours to reflux in 60 cm3 of ethanol and8.5 cm3 of n-propylamine. The solvents are eliminated under reducedpressure at 50° C., the residue is chromatographed on silica (eluent:chdloroform-methanol 7-3) to obtain 2.8 g of2-[2-hydroxy-3-(propylamino)-propoxy]-N-(1H-indol-4-yl) benzamide.

1.7 g of the said base were dissolved in 200 ml of isopropanol and 100ml of methanol at reflux, and 585 mg of oxalic acid were added. Afterpartially concentrating the reaction medium, cooling, filtering anddrying under reduced pressure at 80° C., 1.7 g of the oxalate productmelting at 110° C. were obtained.

    ______________________________________                                        Analysis: C.sub.21 H.sub.25 N.sub.3 O.sub.3, C.sub.2 H.sub.2 O.sub.4 ;        molecular weight = 467.487                                                    ______________________________________                                        Calculated                                                                             % C     60.39   % H   5.95  % N   9.18                               Found            60.2          6.0         9.2                                ______________________________________                                    

EXAMPLE 14N-(1H-indol-4-yl)-2-[2-hydroxy-3-[(1-methylethyl)-amino]propoxy]benzamide

Using the procedure of Example 13, 8.6 ml of isopropylamine were reactedto obtain 2.8 g ofN-(1H-indol-4-yl)-2-[2-hydroxy-3-[(1-methylethyl)-amino]propoxy]benzamide.

Using the procedure of Example 13, 2.8 g of the said base and 960 mg ofoxalic acid were reacted to obtain 1.7 g of the neutral oxalate productmelting 190° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.25 N.sub.3 O.sub.3, 1/2 C.sub.2 H.sub.2 O.sub.4      : molecular weight = 412.469                                                  ______________________________________                                        Calculated                                                                             % C     64.06   % H   6.35  % N   10.19                              Found            63.8          6.5         10.0                               ______________________________________                                    

EXAMPLE 152-[3-[[bis(1-methylethyl)]amino]-2-hydroxypropoxy-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 13, 14 ml of diisopropylamine werereacted while maintaining reflux for 5 hours to obtain 4 g of crudeproduct which was chromatographed over silica (eluant: chloroform-ethylacetate-trimethylamine 6-3-1) and crystallized from ethyl acetate toobtain 2.4 g of2-[3-[[bis(1-methylethyl)]amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamidemelting at 160° C.

    ______________________________________                                        Analysis: C.sub.24 H.sub.31 N.sub.3 O.sub.3 ; molecular weight                ______________________________________                                        = 409.533                                                                     Calculated                                                                             % C     70.39   % H   7.63  % N   10.26                              Found            70.4          7.8         10.2                               ______________________________________                                    

EXAMPLE 162-[3-(diethylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 13, 10 ml of diethylamine were reacted toobtain 3 g of2-[3-(diethylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide.

2.5 g of the said base were dissolved in 65.6 ml of 0.1N hydrochloricacid and 10 ml of methanol were added. The methanol was expelled underreduced pressure and the solution was lyophilized to obtain 2.67 g ofthe hydrochloride product.

    ______________________________________                                        Analysis: C.sub.22 H.sub.27 N.sub.3 O.sub.3 HCl: molecular weight =           417.939                                                                       ______________________________________                                        Calculated                                                                            % C    63.23  % H  6.75 % N  10.05                                                                              % Cl  8.48                          Found          62.9        6.9       9.9        8.7                           ______________________________________                                    

EXAMPLE 172-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamidebenzoate

2 g of the base of Example 4 were dissolved in 200 ml of isopropanol atreflux, and 640 mg of benzoic acid were added. The solution was filteredhot, partially concentrated, cooled and filtered, and the productobtained was dried under reduced pressure at 80° C. After crystallizingfrom isopropanol, 2.0 g of2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamidebenzoate melting at 190° C. were obtained.

    ______________________________________                                        Analysis: C.sub.22 H.sub.27 N.sub.3 O.sub.3, C.sub.7 H.sub.6 O.sub.2          Molecular weight = 503.603                                                    ______________________________________                                        Calculated:                                                                             % C    69.17    % H  6.61   % N  8.34                               Found:           69.4          6.7         8.3                                ______________________________________                                    

EXAMPLE 182-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-[2,3-dihydro-2-oxo-1H-indol-4-yl]benzamideand its neutral oxalate Step A:2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy-N-(3-chloro-1H-indol-4-yl)benzamide

A mixture of 3.3 g of the base of Example 4, 40 ml of acetic acid and1.3 g of N-chloro-succinimide were stirred for 1 hour at ambienttemperature and under an inert atmosphere. The reaction medium wasdiluted with water, alkalinized with ammonia and extracted with ethylacetate. The solvents were eliminated under reduced pressure and theresidue was chromatographed over silica (eluent: ethylacetate-triethylamine, 9-1) to obtain 2.5 g of2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy-N-(3-chloro-1H-indol-4-yl)benzamide.

Step B:2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-[2,3-dihydro-2-oxo-1H-indol-4-yl]benzamide

2.5 g of the product of Step A in 35 ml of ethanol and 70 ml of 1Nhydrochloric acid was refluxed for 1 hour and the reaction mixture wasdiluted with water, alkalinized with sodium hydroxide and extracted withethyl acetate. After elimination of the solvent under reduced pressure,2.5 g of crude product were obtained with crystallized spontaneouslyfrom a mixture of solvents: chloroform-ethyl acetate-triethylamine(6-3-1) to obtain 1.9 g of2-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-[2,3-dihydro-2-oxo-1H-indol-4-yl]benzamidemelting at 160° C.

1.9 g of the said base were dissolved in 300 ml of isopropanol and 100ml of methanol at reflux, and 600 mg of oxalic acid were added. Refluxwas maintained for 15 minutes, after which the reaction medium wascooled and partially concentrated. The crude expected product wascooled, filtered and dried under reduced pressure. After crystallizingfrom a mixture of isopropanol and methanol (1-3), 1.8 g of the oxalatewere obtained melting at 234° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.27 N.sub.3 O.sub.4, 1/2C.sub.2 H.sub.2 O.sub.4 :     molecular weight = 442.495                                                    ______________________________________                                        Calculated:                                                                            % C     62.43   % H   6.38  % N   9.50                               Found:           62.2          6.4         9.3                                ______________________________________                                    

EXAMPLE 192-[3-(4-methyl-1-piperazinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide

1.8 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 36 ml ofethanol and 6.5 ml of N-methyl piperazine was refluxed for 1 hour andthe solvents were eliminated under reduced pressure. The residue waschromatographed over silica (eluent: chloroform-ethanol, 9-1) to obtain1.77 g of2-[3-(4-methyl-1-piperazinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamid

1.7 g of the said base were dissolved in 100 ml of isopropanol and 524mg of oxalic acid were added. The product obtained was filtered off anddried under reduced pressure at 70° C. After crystallizing fromisopropanol, 0.96 g of the oxalate melting at 130° C. (decomposes) wereobtained.

    ______________________________________                                        Analysis: C.sub.23 H.sub.28 N.sub.4 O.sub.3, C.sub.2 H.sub.2 O.sub.4          molecular weight = 498.54                                                     ______________________________________                                        Calculated:                                                                             % C    60.23    % H  6.07   % N  11.24                              Found:           60.3          6.3         11.2                               ______________________________________                                    

EXAMPLE 202-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

1.6 g of 2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)]-benzamide in 36 mlof ethanol was refluxed for 4 hours with 1.82 ml of(methoxyphenyl)piperazine and the solvent was eliminated under reducedpressure. The residue was purified by chromatography over silica(eluent: chloroform-ethyl acetate-triethylamine, 6-3-1) to obtain 1.85 gof2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      Infl. at 235 nm                                                                             E.sub.1.sup.1 = 449                                                                         ε = 22,400                                Max. at 287 nm                                                                              E.sub.1.sup.1 = 222                                                                         ε = 11,100                                Infl. at 294 nm                                                                             E.sub.1.sup.1 = 215                                             Infl. at 310 nm                                                                             E.sub.1.sup.1 = 179                                                                         ε = 8,900                                 IR Spectrum (chloroform):                                                     OH free       3600 cm.sup.-1                                                  CNH           3481 cm.sup.-1 - 3373 cm.sup.-1                                  ##STR44##    1661 cm.sup.-1                                                  CC + aromatic +                                                                             1623 cm.sup.-1 - 1600 cm.sup.-1 - 1587 cm.sup.-1                amide II                                                                                    1538 cm.sup.-1 - 1500 cm.sup.-1 - 1485 cm.sup.-1                ______________________________________                                    

EXAMPLE 212-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

4 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 48 ml ofethanol were refluxed for 1 hour with 6.57 ml of dimethoxyphenylethylamine and the solvent was eliminated under reduced pressure. Theresidue was purified by chromatography over silica (eluent:chloroform-methanol, 9-1) to obtain 4.60 g of2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-amino]-2-hydroxypropoxy]-(1H-indol-4-yl)benzamide.

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      Infl. at 218 nm                                                                             E.sub.1.sup.1 = 921                                             Infl. at 230 nm                                                                             E.sub.1.sup.1 = 528                                                                         ε = 25,800                                Max. at 288 nm                                                                              E.sub.1.sup.1 = 222                                                                         ε = 10,900                                Max. at 299 nm                                                                              E.sub.1.sup.1 = 211                                                                         ε = 10,300                                Infl. at 310 nm                                                                             E.sub.1.sup.1 = 187                                                                         ε = 9,150                                 IR Spectrum (chloroform):                                                     secondary amide                                                               NH                 3360 cm.sup.-1                                             CO                 1659 cm.sup.-1                                             amide II           1534 cm.sup.-1                                             aromatic           1623 cm.sup.-1 - 1601 cm.sup.-1 -                                             1587 cm.sup.-1                                              ##STR45##         1516 cm.sup.-1                                             methoxy            2837 cm.sup.-1                                             ______________________________________                                    

EXAMPLE 222-[3-(cyclohexylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 20 ml ofethanol was refluxed for 2 hours with 1.86 ml of cyclohexylamine and thesolvent was eliminated under reduced pressure. The residue waschromatographed over silica (eluent: chloroform-methanol 9-1) to obtain1.97 g of2-[3-(cyclohexylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      ______________________________________                                        Infl. at 216 nm E.sub.1.sup.1 = 832                                           Infl. at 234 nm E.sub.1.sup.1 = 320                                           Infl. at 270 nm E.sub.1.sup.1 = 113                                           Max. at 296 nm  E.sub.1.sup.1 = 212                                                                        ε = 8,650                                Infl. at 304 nm E.sub.1.sup.1 = 199                                           ______________________________________                                        IR Spectrum (chloroform):                                                     ______________________________________                                        NH indole   3480 cm.sup.-1                                                    Amide       1660 cm.sup.-1                                                    Amide II    1536 cm.sup.-1                                                    Aromatics   1624 cm.sup.-1 -1600 .sup.cm- 1 -1588 cm.sup.-1 -1503                         cm.sup.-1 -1485 cm.sup.-1                                         ______________________________________                                    

EXAMPLE 234-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamideStep A: 4-[N-(1H-indol-4-yl)amido]phenol

Under an inert atmosphere, 42 ml of tri-isobutylaluminum in solution intoluene (1.1M) were added slowly to a solution of 3 g of 4-amino-indolein 100 ml of chloroform and 3.5 g of methyl p-hydroxybenzoate in 50 mlof chloroform were then added, followed by reflux for 24 hours. Aftercooling, 200 ml of 2N hydrochloric acid were added with stirring for 30minutes and the precipitate was filtered off, washed with water anddried under reduced pressure at 80° C. to obtain 4.9 g of4-[N-(1H-indol-4-yl)amido]phenol.

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      ______________________________________                                        Max. at 212 nm  E.sub.1.sup.1 = 1455                                                                       ε = 36,700                               Max. at 256 nm  E.sub.1.sup.1 = 557                                                                        ε = 14,000                               Max. at 277 nm  E.sub.1.sup.1 = 438                                                                        ε = 11,000                               Max. at 284 nm  E.sub.1.sup.1 = 444                                                                        ε = 11,200                               Infl. at 294 nm E.sub.1.sup.1 = 432                                           ______________________________________                                    

Step B: 4-[(2-oxiranyl)methoxy]-N-(1H-(indol-4-yl)]-benzamide

Using the procedure of Example 1, 5.37 g of4-[N-(1H-indol-4-yl)amido]phenol and 25.8 ml of epichlorhydrin werereacted and after chromatography over silica (eluent: chloroform-ethylacetate-triethylamine 6-3-1) and triturating in isopropyl ether, 2.9 gof 4-[(2-oxiranyl)methoxy]-N-(1H-(indol-4-yl)]-benzamide melting at 170°C. were recovered.

Step C:4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxyl]-N-(1H-indol-4-yl)-benzamide

Using the procedure of Step B of Example 1, 2.9 g of the product of StepB were reacted to obtain 3.5 g of4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamidemelting at 212° C.

2.9 g of the said base were dissolved in 300 ml of isopropanol atreflux, and 0.88 g of fumaric acid and then 200 ml of methanol wereadded. Reflux was continued for 30 minutes and the reaction medium waspartially concentrated, then cooled and filtered under reduced pressureat 80° C. to obtain 2.3 g of crude product. After crystallization froman ethanol-methanol-water mixture (10-10-1), 1.8 g of the neutralfumarate melting <270° C. were obtained.

    ______________________________________                                        Analysis: C.sub.22 H.sub.27 N.sub.3 O.sub.2, 1/2C.sub.4 H.sub.4 O.sub.4 :     molecular weight = 439.516                                                    ______________________________________                                        Calculated:                                                                             % C    65.59    % H  6.65   % N  9.56                               Found:           65.3          6.7         9.6                                ______________________________________                                    

EXAMPLE 244-chloro-2-[3-[(1,1-dimethylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamideStep A: 5-chloro-2-[N-(1H-indol-4-yl)amido]phenol

Under an inert atmosphere, a solution of 5.28 g of 4-aminoindole, 100 mlof tetrahydrofuran, 6.9 g of 4-chlorosalicylic acid and 9.06 g ofdicyclohexylcarbodiimide was heated to reflux and the dicyclohexylureaformed was filtered off. The solvent was expelled under reduced pressureat 50° C. and after chromatography over silica (eluent: chloroform-ethylacetate, 9-1), the residue was triturated with ether and dried to obtain5.55 g of 5-chloro-2-[N-(1H-indol-4-yl)amido]phenol melting at 245° C.

    ______________________________________                                        Analysis: C.sub.15 H.sub.11 N.sub.2 ClO.sub.2 : Molecular weight =            ______________________________________                                        286.720                                                                       Calculated:                                                                           % C    62.84  % H  3.87 % N  9.77 % Cl  12.36                         Found:         62.5        4.0       9.7        12.3                          ______________________________________                                    

Step B: 4-chloro-2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide

Under an inert atmosphere, a solution of 4.5 g of5-chloro-2-[N-(1H-indol-4-yl)]amido phenol in 150 ml of acetone washeated to reflux with 2.2 g of potassium carbonate and 12.5 ml ofepichlorhydrin and the product crystallized out of the reaction medium.The solvent was eliminated under reduced pressure at 50° C. and theresidue was taken up in water, filtered and dried under reduced pressureat 80° C. to obtain 5 g of4-chloro-2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide melting at194° C.

Step C:4-chloro-2-[3-[(1,1-dimethylethylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

3 g of the product of Step B was refluxed for 2 hours in 100 ml ofethanol and 7.6 ml of terbutylamine and the solvent was expelled underreduced pressure at 50° C. After chromatography over silica (eluent:chloroform-methanol-triethyamine 8-1-1), 5 g of4-chloro-2-[-3-[(1,1-dimethylethylamino]-2-hydroxypropoxy]-N-(1H-indol-4-)-benzamidewere obtained.

5 g of the said base were dissolved in 300 ml of isopropanol and 300 mlof methanol at reflux and then 1.5 g of oxalic acid were added andheating was maintained for 15 minutes. After partially concentrating,cooling, filtering and drying under reduced pressure at 80° C., 4.4 g ofthe oxalate melting at 254° C. were obtained.

    ______________________________________                                        Analysis: C.sub.22 H.sub.26 N.sub.3 ClO.sub.3, 1/2C.sub.2 H.sub.2 O.sub.4     : molecular weight = 460,941                                                  ______________________________________                                        Calculated:                                                                           % C    59.93  % H  5.90 % N  9.12 % Cl  7.69                          Found:         59.9        6.1       8.9        7.6                           ______________________________________                                    

EXAMPLE 252-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-5-methoxy-benzamideStep A: 4-methoxy-2-[N-(1H-indol-4-yl)amido]phenol

Under an inert atmosphere, 3.96 of 4-amino indole in 70 ml oftetrahydrofuran were refluxed with 5 g of 5-methoxy-salicylic acid and6.18 g of dicyclohexylcarbodiimide. A further 618 mg ofdicyclohexycarbodiimide were added and stirring was continued at ambienttemperature for 20 hours. After filtering, the solvent was eliminatedunder reduced pressure at 50° C. and the residue was taken up in 300 mlof ethyl acetate. The organic phase was washed with 2N hydrochloricacid, then with a saturated aqueous solution of sodium chloride, dried,and the solvent was evaporated under reduced pressure at 50° C. toobtain 9.4 g of crude product. It was purified by chromatography oversilica (eluent: chloroform-ethyl acetate, 9-1), was triturated inisopropyl ether, filtered and dried to obtain 4.7 g of4-methoxy-2-[N-(1H-indol-4-yl)amido]phenol melting at 225° C.

Step B: 5-methoxy-2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide

Under an inert atmosphere, 4.5 g of4-methoxy-2-[N-(1H-indol-4-yl)-amido]phenol in 150 ml of acetone washeated to reflux for 20 hours with 2.2 g of potassium carbonate and 12.5ml of epichlorhydrine. The potassium carbonate was filtered off, thesolvent was expelled under reduced pressure at 50° C., and the residuewas chromatographed over silica (eluent: chloroform-ethyl acetate, 9-1).5.4 g of product were collected which was triturated in ether, filteredand dried under reduced pressure to obtain 5 g of the expected product.m.p.=122° C.

Step C: 2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-5-methoxy-benzamide

By operating as in Step C of Example 24, using 5 g of the product fromStep B above at the start, 4.9 g of the expected product were obtained.

By operating as in Step C of Example 24 at the start from 4.9 g of thebase obtained above, 3.2 g of the oxalate were obtained. m.p.=254° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.29 N.sub.3 O.sub.4, 1/2C.sub.2 H.sub.2 O.sub.4 :     molecular weight = 456.523                                                    ______________________________________                                        Calculated:                                                                             % C    63.14    % H  6.62   % N  9.20                               Found:           62.9          6.7         9.0                                ______________________________________                                    

EXAMPLE 262-[3-(cyclohexylmethyl)amino]-2-hydroxypropoxyl]-N-(1H-indol-4-yl)-benzamid

A solution of 2.5 g of2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 50 ml of ethanolin the presence of 1.147 g of cyclohexane methylamine was refluxed for 2hours and 15 minutes and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica (eluent: methylenechloride-methanol, 9-1) to obtain 1.97 g of2-[3-(cyclohexylmethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide.

    ______________________________________                                        U.V Spectrum (ethanol):                                                       ______________________________________                                        Infl. at 215 nm E.sub.1.sup.1 = 385                                           Infl. at 234 nm E.sub.1.sup.1 = 365                                           Infl. at 269 nm E.sub.1.sup.1 = 128                                           Infl. at 292 nm E.sub.1.sup.1 = 229                                           Max. at 297 nm  E.sub.1.sup.1 = 237                                                                        ε = 10,000                               Infl. at 310 nm E.sub.1.sup.1 = 211                                           ______________________________________                                    

EXAMPLE 272-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

Under an inert atmosphere, a solution of 0.2 g of2[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamidein 5 ml of methanol in the presence of 0.1 ml of formaldehyde with 40%of water was admixed with a solution of 26 mg of sodium cyanoborohydrideand 27.2 mg of zinc chloride in 5 ml of methanol and the reactionmixture was left for 2 hours at ambient temperature. 5 ml of 0.1N sodiumhydroxide were added, and the mixture was extracted with ethyl acetate.The organic phase was washed with water, dried, and the solvents wereeliminated under reduced pressure to obtain 0.230 g of crude product. Itwas purified by chromatography over silica (eluent: chloroform-ethylacetate-triethylamine, 6-3-1) to obtain 0.150 g of2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      ______________________________________                                        Infl. at 218 nm E.sub.1.sup.1 = 794                                           Infl. at 230 nm E.sub.1.sup.1 = 429                                           Max. at 286 nm  E.sub.1.sup.1 = 181                                           Max. at 298 nm  E.sub.1.sup.1 = 176                                                                        ε = 8,850                                Infl. at 310 nm E.sub.1.sup.1 = 158                                           Infl. at 318 nm E.sub.1.sup.1 = 147                                           ______________________________________                                    

EXAMPLE 282-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideand its neutral oxalate Step A: 2-hydroxy-N-(1H-indol-4-yl)benzamide

92 ml of a solution of 1.1 mol/l of triisobutylaluminum in toluene wereadded slowly with stirring under an inert atmosphere to a solution of6.6 g of 4-aminoindole in 250 ml of chloroform. 9.6 ml of methylsalicylate were then added and the mixture was refluxed for 20 hours andthen cooled to room temperature. 300 ml of N hydrochloric acid and 300ml of methylene chloride were added and the organic phase was washedwith water, dried, and evaporated to dryness under reduced pressure at50° C. The residue was made into a paste with ether, filtered and driedat 60° C. under reduced pressure to obtain 9.4 g of2-hydroxy-N-(1H-indol-4-yl)benzamide melting at ≃232° C.

    ______________________________________                                        UV Spectrum (ethanol):                                                        ______________________________________                                        Infl. 216 nm    E.sub.1.sup.1 = 1,595                                         Infl. 233 nm    E.sub.1.sup.1 = 680                                                                        ε = 17,200                               Infl. 262 nm    E.sub.1.sup.1 = 187                                           Infl. 303 nm    E.sub.1.sup.1 = 482                                                                        ε 12,200                                 Infl. 314 nm    E.sub.1.sup.1 = 494                                                                        ε = 12,500                               ______________________________________                                    

Step B: 2-[(2-Oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide

A solution of 3.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 1.9 g ofpotassium carbonate in 100 ml of acetone was refluxed for 30 hours underan inert atmosphere with 11 ml of epichlorohydrin and the insolublematerial was filtered off. The filtrate was evaporated to dryness andthe residue was purified by chromatography over silica (eluent:chloroform/acetone/TEA 6:3:1). Fractions having a Rf=0.45 wereevaporated to dryness and the residue was empasted with ether, filteredand dried under reduced pressure at 60° C. to obtain 3.65 g of2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide melting at 171° C.

Step C:2-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy)-N-(1H-indol-4-yl)benzamide

3.5 g of the product of Step B dissolved in 35 ml of ethanol wasrefluxed with stirring and under an inert atmosphere for 5 hours with 3ml of tert-pentyl-amine and the solvent was evaporated off. The residuewas purified by chromatography over silica (eluant: methylenechloride/methanol 9:1) to obtain 3.5 g of2-[3-[1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide.

Formation of the Neutral Oxalate

2.4 g of the said base were dissolved in 20 ml of ethanol and 0.245 g ofdehydrated oxalic acid were added. The salt formed was filtered off,dried and crystallized from ethanol to obtain 1.83 g of the expectedoxalate melting at 180° C.

EXAMPLE 292-[3-(4-Morpholinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Step C of Example 28, 4 g of the product of StepB of Example 28 and 1.7 ml of morpholine were reacted to obtain 4.12 gof 2-[3-(4-morpholinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideafter chromatography over silica (eluant: chloroform/ethylacetate/triethylamine 6:3:1).

The hydrochloride was prepared with a saturated solution of hydrochloricacid in methylene chloride and the hydrochloride, after crystallizationfrom ethanol, melted at 210° C.

EXAMPLE 302-[3-[(1,1-dimethylpropyl)amino]-propoxy]-N-(1H-indol-4-yl)benzamideStep A: 2-(3-Chloropropoxy)-N-(1H-indol-4-yl)benzamide

A solution of 5 g of 2-hydroxy-N-(1H-indol-4-yl)-benzamide, 400 ml oftetrahydrofuran, 1.8 ml of 3-chloropropanol and 5.7 g oftriphenylphosphine was prepared with stirring and under an inertatmosphere and 3.4 ml of ethyl azodicarboxylate were added slowly. Themixture stood for 5 hours with stirring and 5.7 g of triphenylphosphineand 1.8 ml of 3-chloropropanol were added, followed by 3.4 ml of ethylazodicarboxylate added slowly. The mixture stood again with stirring for15 hours and was evaporated to dryness. The residue was purified bychromatography over silica (eluant: benzene/ethyl acetate 95:5) and thefractions having a Rf=0.15 were evaporated to dryness. The residue wasempasted with ether, filtered and dried under reduced pressure to obtain5.5 g of 2-(3-chloropropoxy)-N-(1H-indol-4-yl)benzamide melting at 140°C.

Step B:2-[3-[(1,1-dimethylpropyl)amino]-propoxy)-N-(1H-indol-4-yl)benzamide

2 g of the product of Step A in 20 ml of ethanol were heated to 120° C.for 5 hours with 2 ml of tert-pentylamine and in the presence of 0.84 gof potassium carbonate, the mixture was filtered. The solvent wasevaporated off and the residue was purified by chromatography on silica(eluant: methylene chloride/methanol 9:1) to obtain 2 g of2-[3-[(1,1-dimethylpropyl)amino]-propoxy)-N-(1H-indol-4-yl)benzamide.

Hydrochloride

1.45 g of the base were dissolved in 20 ml of isopropanol at 50° C. anda saturated solution of hydrochloric acid in ethyl acetate was addeduntil the pH was acid. The mixture was chilled, filtered and dried andthe product was crystallized from isopropanol to obtain 1.7 g of theexpected hydrochloride melting at 216° C.

EXAMPLE 31 2-[3-(Cyclohexylamino)propoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 30 replacing tert-pentylamine bycyclohexylamine and chromatography on silica (eluant: CHCl₃ /ethylacetate/TEA 6:3:1), 2.1 g of2-[3-(cyclohexylamino)propoxy]-N-(1H-indol-4-yl)benzamide melting at148° C. were obtained, and the hydrochloride which melted at 214° C.after crystallization from isopropanol was then formed.

EXAMPLE 322-[3-[Cyclohexylmethylamino]-propoxy)-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 30, but replacing tert-pentylamine withcyclohexylmethylamine,2-[3-[cyclohexylaethylamino]propoxy]-N-(1H-indol-4-yl)benzamide wasobtained, and then its hydrochloride which was crystallized from ethanolmelting at 228° C.

EXAMPLE 332[4-[1,1-Dimethylethylamino]butoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 30 but at 50° C. and replacingtert-pentylamine by tert-butylamine and2-(3-chloropropoxy)-N-1H-indol-4-yl)benzamide by2-(4-bromobutoxy)-N-(1H-indol4-yl)benzamide, and with chromatography onsilica (eluant: CHCl₃ /acetone/TEA of 6:3:1), the residue was taken upin ether to obtain2-[4-[1,1-dimethylethylamino]butoxy]-N-(1H-indol-4-yl)benzamide meltingat 147° C. The acid fumarate, which melted at 224°-225° C. withsublimation after crystallization from ethanol, was prepared.

Preparation of 2-(4-bromobuoxy)-N-(1H-indol-4-yl)benzamide

A suspension of 7.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 8.28 gof potassium carbonate in 150 ml of acetone was refluxed for 75 minuteswith 18 ml of 1,4-dibromobutane and the mixture was cooled. Theprecipitate was filtered off and rinsed with acetone and the filtratewas evaporated to dryness. The residue was purified by chromatographyover silica (eluant: methylene chloride/ethyl acetate 9:1), followed bycrystallization from ethyl acetate to obtain2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide melting at 135° C.

EXAMPLE 342-[3-[1,1-Dimethylethylamino]-2-hydroxypropoxy]-N-(1-methyl-1H-indol-4-yl)benzamideStep A: 2-[(2-Oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)-benzamide

Using the procedure of Example 28, Step A,2-hydroxy-N-(1-methyl-1H-indol-4-yl)-benzamide was reacted to obtain2-[2-Oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)benzamide melting at160° C.

Step B

Using the procedure of Example 28, Step B, the product of Step A andreplacing tert-pentylamine by tert-butylamine were reacted to obtain2-[(2-oxiranyl)methoxy]-N-(1-methyl-H-indol-4-yl)-benzamide melting at130° C. and the hydrochloride, which melted at 195° C. aftercrystallization from isopropanol, was prepared.

Preparation of 2-hydroxy-N-(1-methyl-1H-indol-4-yl)benzamide

A solution of 5 g of 1-methyl-1H-indol-4-amine [prepared according toLey (J. Chem. Soc. Chem. Com. (1982) p. 1356], 4.7 g of salicylic acidand 7 g of dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran wasrefluxed for 24 hours and 20% of salicylic acid and ofdicyclohexylcarbodiimide were added after 5 hours of refluxing. Themixture was filtered and the filtrate was evaporated under reducedpressure. The residue was purified by chromatography over silica(eluant: methylene chloride) to obtain 5.5 g of2-hydroxy-N-(1-methyl-1H-indol-4-yl)benzamide melting at 211° C.

EXAMPLE 352-[3-[1,1-Dimethyl-2-propynylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Step C of Example 28, 4 g of the product of StepB of Example 1 and 1.5 ml of 1,1-dimethylpropargylamine were reacted toobtain 3.77 g of2-[3-[1,1-dimethyl-2-propynylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideafter chromatography on silica (eluant: chloroform/ethylacetate/triethylamine 6:3:1).

Neutral Oxalate

3.09 g of the said product were dissolved in 100 ml of ethanol and 0.497g of oxalic acid were added. The mixture was chilled, filtered and driedunder reduced pressure at 80° C. The product was crystallized fromethanol to obtain 2.5 g of the neutral oxalate melting at 160° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.25 N.sub.3 O.sub.3 ; molecular weight                ______________________________________                                        = 872.984                                                                     Calculated:                                                                             % C    66.04    % H  6.00   % N  9.63                               Found:           65.9          6.0         9.5                                ______________________________________                                    

EXAMPLE 362-[2-Hydroxy-3-[1,1,3,3-tetramethylbutyl-amino]propoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 28, Step C, 5 g of the product of Step Bof Example 28 and 4.9 ml of tert-octylamine were reacted to obtain 4.27g of2-[2-Hydroxy-3-[1,1,3,3-tetramethylbutyl-amino]propoxy]-N-(1H-indol-4-yl)benzamidemelting at 140° C.

    ______________________________________                                        Analysis: C.sub.26 H.sub.35 N.sub.3 O.sub.3 ; molecular weight                ______________________________________                                        = 437.587                                                                     Calculated:                                                                             % C    71.37    % H  8.06   % N  9.60                               Found:           71.6          8.3         9.5                                ______________________________________                                    

EXAMPLE 372-[3-[1,1-Dimethyl-2-hydroxyethylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 28, Step C, 4 g of the product of Step Bof Example 28 and 1.3 ml of 2-amino-2-methyl-1-propanol were reacted toobtain 3.33 g of2-[3-[1,1-dimethyl-2-hydroxyethylamino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamideand it was converted to the neutral oxalate as described in Example 35.2.8 g of expected oxalate was obtained melting at 180° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.27 N.sub.3 O.sub.4 ; molecular weight                ______________________________________                                        = 884.99                                                                      Calculated:                                                                             % C    62.43    % H  6.38   % N  9.50                               Found:           62.3          6.6         9.4                                ______________________________________                                    

EXAMPLE 38 N-(1H-Indol-4-yl)-2-[3-(propylamino)propoxy]-benzamide

Using the procedure of Step B of Example 30, 4.5 g of the product ofStep A of Example 30 and 6.5 ml of N-propylamine were reacted to obtainafter chromatography over silica (eluant: chloroform/ethylacetate/triethylamine 6:3:1), 3.20 g ofN-(1H-indol-4-yl)-2-[3-(propylamino)propoxy]-benzamide. 3 g of the basewere converted to the hydrochloride as described in Example 30 to obtain2 g of hydrochloride melting at 202° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.25 N.sub.3 O.sub.2 ; molecular weight                ______________________________________                                        = 387.913                                                                     Calculated:                                                                           % C    65.02  % H  6.76 % Cl 9.14 % N   10.83                         Found:         64.9        6.7       9.3        10.7                          ______________________________________                                    

EXAMPLE 39N-(1H-Indol-4-yl)-2-[3-(1-methylethyl)amino]-propoxy]benzamide

Using the procedure of Example 38, 4 g of starting substance and 10 mlof isopropylamine were reacted to obtain 2.93 g ofN-(1H-indol-4-yl)-2-[3-(1-methylethyl)amino]-propoxy]benzamide and 1.79g of its hydrochloride from 2.6 g of base which melted at 180° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.25 N.sub.3 O.sub.2 ; molecular weight                ______________________________________                                        = 387.913                                                                     Calculated:                                                                           % C    65.02  % H  6.76 % Cl  9.14 % N  10.83                         Found:         65.0        6.9        9.0       10.8                          ______________________________________                                    

EXAMPLE 402-[3-[1,1-Dimethyl-2-hydroxyethylamino]-propoxy]-N-indol-4-yl)benzamide

Using the procedure of Example 30 Step B, 3 g of product of Step A ofExample 30 and 5 ml of 2-amino-2-methyl-1-propanol were reacted toobtain after chromatography over silica (eluant:chloroform/methanol/triethylamine 90:5:5), 2.1 g of2-[3-[1,1-dimethyl-2-hydroxyethylamino]propoxy]-N-(1H-indol-4-yl)benzamide

Neutral Fumarate

Using 1.85 of the said base and 5.63 g of fumaric acid, 1.323 g of theneutral fumarate melting at 186° C. were obtained.

    ______________________________________                                        Analysis: (C.sub.22 H.sub.27 N.sub.3 O.sub.3).sub.2.C.sub.4 H.sub.4           O.sub.4 ; molecular weight = 879.031                                          ______________________________________                                        Calculated:                                                                              % C    65.59   % H  6.65  % N  9.56                                Found:            65.5         6.9        9.3                                 ______________________________________                                    

EXAMPLE 41N-[2-(3-[Isopropylamino]propoxy]phenyl]-1H-indole-4-carboxamide Step A:N-[2-(3-Bromopropoxy)phenyl]-1H-indole-4-carboxamide

A suspension of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and2.18 g of potassium carbonate in 20 ml of acetone was admixed with 3.2ml of 1,3-dibromopropane and the mixture was refluxed for 90 minutes andwas filtered. The solvent was evaporated under reduced pressure and theresidue was chromatographed over silica (eluant: chloroform/ethylacetate/triethylamine 6:3:1 to obtain 2.37 g ofN-[2-[3-bromopropoxy)phenyl]-1H-indole-4-carboxamide melting at 145° C.

Step B:N-[2-[3-[(1-Methylethyl)amino]propoxy)phenyl]-1H-indole-4-carboxide

Using the procedure of Step B of Example 30, 4 g of product of Step Aand 4.5 ml of isopropylamine were reacted to obtain after chromatographysilica (eluant: chloroform/ethyl acetate/triethylamine over 6:3:1), 2.91g ofN-[2-[3-[(1-methylethyl)amino]propoxy)phenyl]-1H-indole-4-carboxide, andthen 2.5 g of its hydrochloride melting at 234° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.25 N.sub.3 O.sub.2.HCl                               ______________________________________                                        Calculated:                                                                           % C    65.02  % H  6.76 % Cl  9.14 % N  10.83                         Found:         65.3        6.8        9.3       10.7                          ______________________________________                                    

EXAMPLE 42N-[2-[3-(Cyclopentylamino)propoxy]phenyl]-1H-indol-4-carboxamide

Using the procedure of Example 41, Step B, 4 g of the product of Step Aof Example 41 and 2.11 ml of cyclopentylamine were reacted to obtain 3.3g of N-[2-[3-(cyclopentylamino)propoxy]phenyl]-1H-indol-4-carboxamideand then 2.8 g of its hydrochloride melting at 244° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.27 N.sub.3 O.sub.2.HCl; molecular weight =           ______________________________________                                        413.95                                                                        Calculated:                                                                           % C    66.74  % H  6.82 % Cl  8.56 % N  10.15                         Found:         66.9        6.8        8.4        9.9                          ______________________________________                                    

EXAMPLE 43N-[2-[3-(Cyclohexylamino)propoxy]phenyl]-1H-indole-4-carboxamide

Using the procedure of Example 41, Step B, 2.5 g of the product of StepB of Example 41 and 1.5 ml of cyclohexylamine were reacted to obtain 1.8g of N-[2-[3-(cyclohexylamino)propoxy]phenyl]-1H-indole-4-carboxamideand 1.7 g of its hydrochloride melting at 260° C.

    ______________________________________                                        Analysis: C.sub.24 H.sub.29 N.sub.3 O.sub.2.HCl; molecular weight =           427.979                                                                       ______________________________________                                        Calculated:                                                                           % C    67.35  % H  7.06 % Cl  8.28 % N  9.82                          Found:         67.1        7.1        8.4       9.7                           ______________________________________                                    

EXAMPLE 44N-[2-[3-[1,1-Dimethylpropylamino]propoxy]phenyl]-1H-indole-4-carboxamide

Using the procedure of Example 41, Step B, 4 g of the compound of Step Bof Example 41 and 5 ml of tert-amylamine were reacted to obtain 2.90 gofN-[2-[3-[1,1-dimethylpropylamino]propoxy]phenyl]-1H-indole-4-carboxamideand then 2.5 g of its hydrochloride from 2.7 g of base melting at 230°C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.29 N.sub.3 O.sub.2.HCl; molecular weight =           415.967                                                                       ______________________________________                                        Calculated:                                                                           % C    66.41  % H  7.27 % Cl  8.52 % N  10.1                          Found:         66.4        7.3        8.6       10.1                          ______________________________________                                    

EXAMPLE 45N-[2-[3-[(2-(3,4-Dimethoxyphenyl)ethyl]-amino]propoxy]phenoxy]-1H-indole-4-carboxamide

Using the procedure of Example 41, Step B, 3 g of the compound of Step Bof Example 14 and 2.31 ml of homoveratrylamine to obtain afterchromatography over silica (eluant: chloroform/methanol 9:1), 2.75 g ofN-[2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-amino]propoxy]phenyl]-1H-indole-4-carboxamideand then 1.75 g of its hydrochloride from 2.55 g of base melting at 182°C.

    ______________________________________                                        Analysis: C.sub.20 H.sub.31 N.sub.3 O.sub.4.HCl; molecular weight =           510.038                                                                       ______________________________________                                        Calculated:                                                                           % C    65.94  % H  6.32 % Cl  6.95 % N  8.24                          Found:         65.9        6.2        6.7       8.2                           ______________________________________                                    

EXAMPLE 462-[2-Hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Example 28 of Step C, 3.08 g of2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide of step B of Example28, and 5.2 g of 1-(diphenylmethyl)piperazine were reacted to obtainafter chromatography over silica (eluant: chloroform/ethyl acetate 7:3),5.12 g of2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)benzamide,and then 3.22 g of its neutral oxalate from 4.36 g of base melting at170° C.

    ______________________________________                                        Analysis: C.sub.35 H.sub.36 N.sub.4 O.sub.3).sub.2.C.sub.2 H.sub.2            O.sub.4 ; molecular weight = 1211.44                                          ______________________________________                                        Calculated:                                                                              % C    71.38   % H  6.15  % N  9.24                                Found:            71.4         6.3        9.1                                 ______________________________________                                    

EXAMPLE 47N-(1H-Indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide

2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide of Example 33,2.71 g of 1-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazine [German PatentNo. 3,347,173] and 0.683 g of sodium carbonate in 25 ml of ethanol wereheated to 60° C. for 10 hours and the mixture is cooled and poured intowater and extracted with ethyl acetate. The extract was washed withwater and dried and the solvents were evaporated under reduced pressure.The residue was chromatographed over silica (eluant:chloroform/acetone/triethylamine 6:3:1) to obtain 3.51 g ofN-(1H-indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide.

Difumarate

Using 2.52 g of the said base and 4.98 mg of fumaric acid, 1.718 g ofits difumarate melting at 183° C. were obtained.

    ______________________________________                                        Analysis: C.sub.34 H.sub.42 N.sub.4 O.sub.5).sub.2.C.sub.8 H.sub.8            O.sub.8 ; molecular weight = 818.895                                          ______________________________________                                        Calculated:                                                                              % C    61.60   % H  6.15  % N  6.84                                Found:            61.3         6.1        6.6                                 ______________________________________                                    

EXAMPLE 482-[3-[(1,1-Dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamidebenzoate

1.11 g of benzoic acid were added to a solution of 3.6 g of the freebase of Step C of Example 28 and the mixture was chilled, filtered anddried under reduced pressure at 90° C. to obtain 3 g of2-[3-[(1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamidebenzoate after crystallization from isopropanol melting at 170° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.29 N.sub.3 O.sub.3 ; molecular weight                ______________________________________                                        = 517.615                                                                     Calculated:                                                                              % C    69.91   % H  6.82  % N  8.12                                Found:            69.9         6.8        8.2                                 ______________________________________                                    

EXAMPLE 492-[2-Hydroxy-3-[4-diphenylmethyl)-1-piperazinyl]propoxy]-N-(1-methyl-1H-indol-4-yl)benzamide

Using the procedure of Example 28, of Step C, 4 g of2-[(2-oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)benzamide of Example34 and and 6.3 g of diphenylmethylpiperazine were reacted to obtain 5.95of2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1-methyl-1H-indol-4-yl)benzamideand then 4.9 g of its hydrochloride melting at 196° C. aftercrystallization from ethanol.

    ______________________________________                                        Analysis: C.sub.36 H.sub.38 N.sub.4 O.sub.3 · HCl ; molecular        weight = 611.19                                                               ______________________________________                                        Calculated:                                                                           % C    70.76  % H  6.43 % Cl  5.80 % N  9.17                          Found:         70.4        6.3        5.9       9.1                           ______________________________________                                    

Using the procedure of already described in the examples, also preparedthe following product to2-[2-hydroxy-3-[[4-bis(4-fluoro-benzyl]-1-piperazinyl]propoxy]phenyl]-N-(1H-indol-4-yl)benzamide.

EXAMPLE 502-[3-(1,1-Dimethylethyl)-amino]-2-hydroxy-propoxy]-N-(1H-indol-4-yl)-5-nitro-benzamideStep A: 2-Hydroxy-5-nitro-N-(1H-indol-4-yl)-benzamide

A mixture of 6 g of 4-amino-indole, 150 ml of tetrahydrofuran, 8.4 g of5-nitro-salicylic acid and 12.5 g of dicyclohexylcarbodiimide wasrefluxed for 3 hours and cooled and filtered. 200 ml of ethyl acetatewere added to the filtrate and excess 4-amino-indole was removed bywashing with 1N hydrochloric acid. The mixture was dried and filteredand the filtrate was evaporated to dryness under reduced pressure at 50°C. to obtain 20 g of a resin. The latter was empasted with a 1-1 mixtureof chloroform and methanol and filtered. The filtrate was evaporated todryness under reduced pressure to obtain 7.5 g of2-hydroxy-5-nitro-N-(1H-indol-4-yl)-benzamide melting at >260° C.

Step B:2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-5-nitro-benzamide

A mixture of 9.8 g of the product of Step A and 40 ml of epibromohydrinwas refluxed for one hour and excess epibromohydrin was removed underreduced presure at 60° C. The resulting resin was taken up in 100 ml ofethanol and 40 ml of tert.-butylamino and the mixture was refluxed for 2hours. The mixture was evaporated to dryness under reduced pressure at60° C. to obtain 78 g of raw product. The latter was chromatographedtwice with successive elutions with fastchloroform-methanol-triethylamine (8-1-1) and thenchloroform-acetone-triethylamine (5-4-1) to obtain 4.4 g of2-[3-(1,1-dimethylethyl)amino]-2-hydroxypropoxy-N-(1H-indol-4-yl)-5-nitro-benzamidemelting at 208° C.

A solution of 3.5 g of the said product in one liter of isopropanol and250 ml of methanol was refluxed and a saturated solution of ethylacetate saturated hydrogen chloride was added until the pH was acidic.The mixture was refluxed for 30 minutes and was concentrated to about500 ml, iced and filtered. The product was dried under reduced pressureat 50° C. to obtain 2.85 g of the hydrochloride melting at >260° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated:                                                                           % C    57.08  % H  5.88 % N  12.10                                                                              % Cl  7.66                          Found:         56.8        6.1       12.0       7.4                           ______________________________________                                    

EXAMPLE 515-Amino-2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamide

A mixture of 142 mg of the product of Example 50, 5 ml of methanol, apinch of Raney nickel and 0.2 ml of hydrazine hydrate was refluxed forone hour and was then filtered. The filtrate was evaporated to drynessunder reduced pressure at 50° C. to obtain 128 mg of5-amino-2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamide.

    ______________________________________                                        U.V. Spectrum (ethanol):                                                      Max. at 219 nm      E.sup.1.sub.1 = 443                                       Max. at 310 nm      E.sup.1.sub.1 = 230                                       U.V. Spectrum (ethanol-N HCl)                                                 Max. at 299 nm      E.sup.1.sub.1 = 208                                                                     ε = 8,200                               Inflex towards 275 and 332 mm                                                 ______________________________________                                    

EXAMPLE 525-Acetylamino-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamideStep A: 5-Amino-2-hydroxy-N-(1H-indol-4-yl)-benzamide

A suspension of 6 g of 5-nitro-2-hydroxy-N-(1H-indol-4-yl)-benzamide ofExample 50, 600 ml of methanol and 15 ml of 64% hydrazine hydrate and 6g of Raney nickel was refluxed for two hours and filtered. The filtratewas evaporated to dryness under pressure at 50° C. and the residue wastaken up in a 1-1 mixture of chloroform and methanol. The mixture wasfiltered and the crystalline product was dried to obtain 4 g of5-amino-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at >260° C.

Step B: 5-Acetylamino-2-acetoxy-N-(1H-indol-4-yl)-benzamide

A suspension of 2.6 g of the product of Step A in 70 ml oftetrahydrofuran was cooled to 0° to 5° C. and then 4.7 ml of aceticanhydride were added. The mixture was held at room temperature for 3hours and was then evaporated to dryness under reduced pressure at 50°C. The residue was taken up in a 1-1 mixture of chloroform-methanol andwas filtered. The product was dried at 80° C. to obtain 2.7 g of5-acetylamino-2-acetoxy-N-(1H-indol-4-yl)-benzamide melting at 263° C.

Step C: 5-Acetylamino-2-hydroxy-N-(1H-indol-4-yl)-benzamide

1.5 g of boron hydride and sodium were added to a suspension of 1.5 g ofthe product of Step B in 150 ml of methanol and the mixture was refluxedfor 2 hours. The methanol was partially removed under reduced pressureat 50° C. and the mixture was diluted with 200 ml of water and 200 ml ofethyl acetate. The mixture was extracted with ethyl acetate and theextracts were dried and evaporated to dryness under reduced pressure at50° C. to obtain 1.35 g of5-acetylamino-2-hydroxy-N-(1H-indol-4-yl)-benzamide which was used as isfor the next step.

Step D: 5-Acetylamino-2-(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)benzamide

A mixture of 3.5 g of the product of Step C, 150 ml of acetone, 1.5 g ofpotassium carbonate and 9 ml of epibromohydrin was refluxed for 2 hoursand after the addition of another 9 ml of epibromohydrin, the mixturewas refluxed for 20 hours and was filtered. The filtrate was washed withacetone and evaporated to dryness under reduced pressure at 50° C. Theresidue was taken up in ether and was filtered. The product was dried at80° C. to obtain 3.4 g of5-acetylamino-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamidemelting at 230° C.

Step E:5-Acetylamino-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamide

A mixture of 3.4 g of the product of Step D, 200 ml of ethanol and 20 mlof tert.-butylamine was refluxed for one hour and was then evaporated todryness under reduced pressure at 50° C. The residue was chromatographedover silica and was eluted with a 8-1-1chloroform-methanol-triethylamine mixture to obtain 3.8 g of5-acetylamino-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamide

2.7 g of the said compound were dissolved in 200 ml of ethanol and 330 gof oxalic acid were added thereto. The mixture was filtered and theproduct was dried under reduced pressure at 80° C. to obtain 2.2 g ofthe neutral oxalate melting at >260° C.

    ______________________________________                                        Analysis: C.sub.24 H.sub.30 N.sub.4 O.sub.4 · 1/2 C.sub.2            H.sub.2 O.sub.4 ; molecular weight = 423.549                                  ______________________________________                                        Calculated:                                                                              % C    62.10   % H  6.46  % N  11.59                               Found:            61.9         6.2        11.5                                ______________________________________                                    

EXAMPLE 532-[3-(1,1-dimethylethyl)-amine]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-4-methoxy-benzamideStep A: 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide

A mixture of 3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 gof 2-hydroxy-4-methoxy-benzoic acid and 6.2 g ofdicyclohexylcarbodiimide was refluxed for 24 hours and was evaporated todryness under reduced pressure at 50° C. The residue was taken up inethyl acetate and excess 4-amino-1H-indole was removed by washing with2N hydrochloric acid. The mixture was evaporated to dryness underreduced pressure and the residue was taken up in ether and dried at 50°C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamidemelting at 190° C.

Step B: 4-Methoxy-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)benzamide

Using the procedure of Step D of Example 52, 5 g of the product of StepA, 150 ml of acetone, 2.45 g of potassium carbonate and 14 ml ofepichlorohydrin were reacted to obtain 7.3 g of4-methoxy-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide meltingat 157° C.

Step C:2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy]-N-(1H-indol-4-yl)-4-methoxy-benzamide

Using the procedure of Step E of Example 52, 6 g of the product of StepB, 100 ml of ethanol, 9.2 ml of tert.-butylamine were refluxed for 3hours to obtain 6.1 g of2-[3-(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-4-methoxy-benzamide.The product was dissolved in 300 ml of refluxing isopropanol and 1.8 gof benzoic acid were added thereto. The mixture was partiallyconcentrated, iced and filtered and the product was dried under reducedpressure to obtain 5.1 g of the benzoate salt melting at 195° C. aftercrystallization from ethanol.

    ______________________________________                                        Analysis: C.sub.23 H.sub.29 N.sub.3 O.sub.4 ; molecular weight                ______________________________________                                        = 533.629                                                                     Calculated:                                                                              % C    67.53   % H  6.61  % N  7.87                                Found:            67.5         6.7        8.0                                 ______________________________________                                    

EXAMPLE 545-Chloro-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamideStep A: 5-chloro-3-hydroxy-N-(1H-indol-4-yl)-benzamide

A mixture of 3.96 g of 4-amino-1H-indole, 75 ml of tetrahydrofuran, 5.16g of 5-chloro-salicyclic acid and 6.2 g of dicyclohexylcarbodiimide wasrefluxed for 2 hours and after the addition of another 0.62 g ofdicyclohexylcarbodiimide, the mixture was refluxed for one hour, cooledand was filtered. The filtrate was evaporated to dryness under reducedpressure at 50° C. and the residue was taken up in ethyl acetate. Thesolution was washed with 2N hydrochloric acid, dried and evaporated todryness under reduced pressure at 50° C. The residue was chromatographedover silica and was eluted with a 9-1 mixture of chloroform-ethylacetate to obtain 3.9 g of5-chloro-3-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 248° C.

Step B: 5-chloro-1-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide

Using the procedure of Step D of Example 52, 3 g of the product of StepA, 100 ml of acetone, 1.47 g of potassium carbonate and 8.3 ml ofepichlorohydrin were reacted to obtain 3.35 g of5-chloro-1-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide melting at175° C.

Step C:5-chloro-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamide

Using the procedure of Step E of Example 52, 3 g of the product of StepB, 60 ml of ethanol and 4.6 ml of tert.-butylamine were reacted toobtain 2.6 g of5-chloro-2-[3-(1,1-dimethylethyl)-amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamideand then 2.4 g of its oxalate melting at >260° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.26 ClN.sub.3 O.sub.3 ; molecular weight =            ______________________________________                                        460.941                                                                       Calculated:                                                                           % C    59.93  % H  5.90 % N  9.12 % Cl  7.69                          Found:         60.2        5.8       9.1        7.9                           ______________________________________                                    

EXAMPLE 55

Tablets were prepared containing 50 mg of the product of Example 50 or50 mg of the neutral oxalate of2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-N-(1H-indol-4-yl)-benzamideand sufficient excipient of lactose, starch, talc and magnesium stearatefor a final weight of 100 mg. Tablets were also prepared containing 100mg of2-[3-(1,1-dimethylethyl)amino]-2-hydroxy-propoxy-(1H-indol-4-yl)-benzamideand sufficient of the said excipient for a final weight of 150 mg.

PHARMACOLOGICAL STUDY

1. Anti-arrhythmic action in the rat

Male rats weighing 300-350 g were anesthetized intra-peritoneally with1.20 g/kg of urethane, then tracheotomized and submitted to artificialrespiration (40-50 breaths of 3 ml/minute). Needles were implantedsubcutaneously so as to record the electro-cardiogram of the rats on theD_(II) derivation signal. The products under test were administeredintravenously or orally.

Five minutes after the administration of the product intravenously or 1hour after administration orally, the jugular vein of the rats wasperfused with 10 μg/minute from 0.2 ml of a solution of aconitine, andthe time of appearance of disturbances of the cardiac rhythm was noted,(10 μg of aconitine corresponding to a perfusion of 0.2 ml of solution).The results are expressed as a percentage of the extension of the timeof appearance of the disturbances of the cardiac rhythm as compared withcontrols, and as a function of the dose of the product under test. Theresults appearing in the following table show that the products of thepresent application are endowed with remarkable anti-arrhythmicproperties.

    ______________________________________                                        Product of      Dose in    Percentage extension                               Example Route   mg/kg      of the time                                        ______________________________________                                        1       IV      0.25         +31                                                              0.5          +41                                                              1            +110                                             2       IV      1            +6                                                               2.5          +57                                              3       IV      2.5          +68                                              4       IV      0.5          +17                                                              1.0          +38                                                              2.5          +124                                                     PO      5            +7                                                               10           +46                                                              25           +81                                              5       IV      0.25         +9                                                               0.5          +36                                                              1            +33                                                              2.5          +61                                                      PO      2.5          +22                                                              5            +32                                                              10           +59                                              6       IV      1            +23                                                              2.5          +41                                                      PO      2.5          +29                                              15      IV      2.5          +25.5                                                            5            +56                                              28              1            +14                                                              2.5          +54                                                              5.0          +95                                              30              2.5          +38                                                              5            +99                                                              10           +147                                             31              1            +24                                                              2.5          +34                                                              5.0          +83                                              32              6.5          +28                                                              1.0          +43                                                              2.5          +71                                                              5.0          +97                                              ______________________________________                                        Product of      Dose in    Percentage of prolongation                         Example         mg/kg      in the time                                        ______________________________________                                        33              5      mg/kg 54%                                                              10     mg/kg 99%                                              34              2.5    mg/kg 12%                                                              5      mg/kg 43%                                                              10     mg/kg 125%                                             36              1      mg/kg 25%                                                              2.5    mg/kg 69%                                              37              1      mg/kg 47%                                                              5      mg/kg 116%                                             38              2.5    mg/kg 42%                                                              5      mg/kg 76%                                                              10     mg/kg 173%                                             40              1      mg/kg 21%                                                              2.5    mg/kg 50%                                              41              1      mg/kg 34%                                                              2.5    mg/kg 57%                                                              5      mg/kg 156%                                             42              1      mg/kg 29%                                                              2.5    mg/kg 86%                                              43              1      mg/kg 49%                                                              2.5    mg/kg 83%                                              44              1      mg/kg 50%                                                              2.5    mg/kg 90%                                                              5      mg/kg 167%                                             45              2.5    mg/kg 60%                                                              5      mg/kg 142%                                                             10     mg/kg 193%                                             46              2.5    mg/kg 67%                                                              5      mg/kg 127%                                                             10     mg/kg 203%                                             47              5      mg/kg 44%                                                              10     mg/kg 67%                                              48              2.5    mg/kg 53%                                                              5      mg/kg 79%                                              50      IV      2.5          +77%                                                             1            +39%                                                             0.5          +17%                                             53      IV      2.5          +38%                                                             1            +10%                                             ______________________________________                                    

2. Affinity for beta₁ -adrenergic receptors

The technique is modelled on that of Mohler et al [Science., Vol. 198,p. 849-851 (1977)]. 10 cortexes removed from the brains of male ratsweighing 150 g on average were homogenized in 90 ml of 0.32M sucrose andafter centrifugation of the homogenized mixture of 1,000 g for 20minutes at 0° C., the supernatant was centrifuged at 30,000 g for 15minutes at 0° to +4° C. The pellet was suspended in 120 ml of 50 mMTris-HCl buffer pH 7.7, and centrifuged at 30,000 g for 15 minutes at 0°to +4° C. The new pellet was suspended in 480 ml of 50 mM Krebs Tris-HClbuffer pH 7.7. 2 ml of the suspension were then incubated for 10 minutesat 37° C. in the presence of [³ H] dihydroalprenolol at a concentrationof 10⁻⁹ M, (i) alone, (ii) with increasing concentrations of the testproduct or (iii) to determine the non-specific binding, withnon-radioactive propanolol at a concentration of 10⁻⁵ M. The incubatedsuspensions were filtered on Whatman GF/C, and the filters were washedthree times with 5 ml of Krebs Tris-HCl buffer pH 7.7 at 0° C.

The radioactivity of the filters was measured by liquid scintillation.The affinity of the test product for beta₁ -adrenergic receptors isgiven relative to propanolol as the reference product.

CD=concentration of propanolol inhibiting 50% of the specific binding of[³ H]dihydroalprenolol.

CX=concentration of the test product inhibiting 50% of the specificbinding of [³ ]dihydroalprenolol.

The relative affinity is given by the relation ##EQU1##

The following results were obtained:

    ______________________________________                                        Product of                                                                    Example       ARL in %                                                        ______________________________________                                        28            28                                                              34            44                                                              48            20                                                              ______________________________________                                    

It is observed that the products of the invention possess exceptionalaffinity for beta₁ -adrenergic receptors.

3. Affinity for beta₂ -adrenergic receptors

The technique was modelled on that of Mohler et al [Science, Vol. 198,p. 849-851 (1977)]. The cerebella removed from the brains of male ratsweighing 150 g on average were homogenized in 90 ml of 0.32M sucrose andafter centrifugation of the homogenized mixture at 1,000 g for 20minutes at 0° C., the supernatant was centrifuged at 30,000 g for 15minutes at 0° to +4° C. The pellet was suspended in 120 ml of 50 mMTris-HCl buffer pH 7.7, and centrifuged at 30,000 g for 15 minutes at 0°to +4° C. The new pellet was suspended in 480 ml of 50 mM Krebs Tris-HClbuffer pH 7.7. 2 ml of suspension were then incubated for 10 minutes at37° C. in the presence of [³ H]dihydroalprenolol at a concentration of10⁻⁹ M, (i) alone, (ii) with increasing concentrations of the testproduct or (iii) to determine the non-specific binding, withnon-radioactive propranolol at a concentration of 10⁻⁵ M. The incubatedsuspensions were filtered on Whatman GF/C, and the filters were washedthree times with 5 ml of Krebs Tris-HCl buffer pH 7.7 at 0° C.

The radioactivity of the filters was removed by liquid scintillation.The affinity of the test product for beta₂ -adrenergic receptors wasgiven relative to propanolol as the reference product.

CD=concentration of propanolol inhibiting 50% of the specific binding of[³ H]dihydroalprenolol.

CX=concentration of the test product inhibiting 50% of the specificbinding of [³ H]dihydroalprenolol.

The relative affinity is given by the relation ##EQU2##

The following results were obtained.

    ______________________________________                                        Product of                                                                    Example       ARL in %                                                        ______________________________________                                        28            15                                                              34            81                                                              48            27                                                              ______________________________________                                    

It is observed that the products of the invention possess exceptionalaffinity for beta₂ -adrenergic receptors

4. Test of calcium-antagonistic activity in vitro

Rat caudal arteries were cut into a spiral connected to tension gaugesand maintained in cells containing 25 ml of Krebs sodium bicarbonatebuffer (NaCl: 120.8 nM; KCl: 5.9 mM; MgCl₂ : 1.2 mM; NaH₂ PO₄ : 1.2 mM;NaHCO₃ : 15.5 mM; glucose: 12.6 mM) at 37° C., gassed with a 95% O₂ /5%CO₂ mixture. The preparations were depolarized with a buffer solutioncontaining K⁺ ions at a concentration of 100 mM (NaCl: 26.7 mM; KCl: 100mM; MgCl₂ : 1.2 mM; NaH₂ PO₄ : 1.2 mM; NaHCO₃ : 15.5 mM; glucose: 12.6mM). Calcium chloride was added in a volume of 250 μl to obtain a seriesof increasing concentrations of Ca²⁺ ions ranging from 0.1 to 3.0 mM.The contractions of the arteries were recorded and a control series werethus established. The operation was repeated with the series of Ca²⁺ions every 15 minutes and the preparation was washed four times aftereach series. When a stable response was obtained, the operation with theseries of Ca²⁺ ions was performed in the presence of differentconcentrations of the test product, until a stable response wasobtained.

The contractions of the arteries depend on the entry of Ca²⁺ ions intothe cells of the smooth muscles, and were caused by the depolarizationof the smooth muscle by the K⁺ ions and by the action of thenoradrenaline released at presynaptic level. By starting the operationagain with arteries denervated by the action of 6-OH-dopamine, thespecific action due to noradrenaline was eliminated.

The results were expressed as IC₅₀ (inhibitory concentration₅₀), theconcentration of the test product which inhibits by 50% the contractiondue to K⁺ ions. From the results recorded in the table below, it isobserved that the products of the invention possess strongcalcium-antagonistic activity.

    ______________________________________                                        Product of                                                                    Example       IC.sub.50 in uM                                                 ______________________________________                                        28            2.5                                                             30            8                                                               31            1.8                                                             32            3.9                                                             33            6.3                                                             34            8.8                                                             35            9                                                               36            0.44                                                            40            8.4                                                             46            0.25                                                            47            2.8                                                             49            3                                                               53            8                                                               54            5.4                                                             ______________________________________                                    

5. Study of the hypotensive activity on anaesthetized normotensive rats

Sprague-Dawley male rats (CR) were anaesthetized intraperitoneally withpentabarbital sodium (60 mg/kg) and a jugular vein was catheterized forthe injection of the product, and a carotid artery was catheterized forrecording the arterial blood pressure. The test product was dissolved in10% ethanol and then injected in a volume of 1 ml/kg. The pressure wasnoted at times 5 minutes and 30 minutes after the injection of theproduct. The table below shows the variations expressed as a percentageof the arterial blood pressure after administration of the test productcompared with the initial control arterial blood pressure.

    ______________________________________                                                            5 mins after                                                                             30 min. after                                  Example  Dose       administration                                                                           administration                                 ______________________________________                                        17       10 mg/kg   -55        -13                                            ______________________________________                                    

6. Study of the acute toxicity

The lethal doses LD₅₀ of the different compounds tested were evaluatedafter administration orally to mice. The maximum dose not causing anymortality in 8 days was called the LD₀ and the following results wereobtained.

    ______________________________________                                        Product of Example                                                                            LD.sub.0 in mg/kg                                             ______________________________________                                        1                80                                                           2                80                                                           4               >400                                                          5                60                                                           6               200                                                           12              >400                                                          15              ≧400                                                   28              >400                                                          30               80                                                           32              100                                                           33              >400                                                          34               80                                                           44              200                                                           46              400                                                           50              200                                                           ______________________________________                                    

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound of the formula ##STR46## wherein R₁ andR form, with the nitrogen atom to which they are attached, ##STR47## inwhich Z is naphthyl, benzyl, phenethyl ##STR48## n₁ is 1, 2, or 3 and X,X₁, X₂, X₃, X₄, X₅ and X₆ are individually selected from the groupconsisting of hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3carbon atoms, halogen, nitro, amino, monoalkylamino or dialkylaminoradical, with the proviso that X, X₁ and X₂ are not all three hydrogen,A is --(CH₂)_(n), --n is 2, 3, 4 or 5 or ##STR49## in which m is 1, 2 or3, B is --CO--NH-- or --NH--CO--, R₃ is hydrogen, alkyl of 1 to 5 carbonatoms, alkoxy of 1 to 3 carbon atoms, chlorine, bronine or iodine, nitroor amino unsubstituted or substituted with an aliphatic acyl of 2 to 5carbon atoms or with alkyl of 1 to 5 carbon atoms, a together with b isan oxo group, or together with c is a second bond between the carbonswhich bear them, b is hydrogen or together with a is an oxo, c ishydrogen or together with a is a second bond between the carbons whichbear them, and R₂ is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl oralkynyl of 2 to 5 carbon atoms or aralkyl of 7 to 12 carbon atomsunsubstituted or substituted with 1, 2 or 3 members of the groupconsisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,methylthio, amino and nitro or cycloalkylalkyl of 4 to 7 carbon atomsand its non-toxic, pharmaceutically acceptable acid addition salts.
 2. Acompound of claim 1 wherein R₂ is hydrogen.
 3. A compound of claim 2wherein a and c form a carbon-carbon bond.
 4. A compound of claim 1wherein R₃ is hydrogen.
 5. A compound of claim 1 wherein ##STR50## is inthe ortho position with respect to B.
 6. A compound of claim 1 wherein Bis ##STR51## with NH next to the indole.
 7. A compound of claim 1wherein R₁ and R₂ together with the nitrogen form ##STR52## in which Zhas the above meaning, A is ##STR53## or --(CH₂)₃ -- or --(CH₂)₄ --, R₃is hydrogen, R₂ is hydrogen or methyl, b is hydrogen and a and ctogether form a second bond between the carbons which bear them.
 8. Acompound of claim 1 selected from the group consisting of2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)-benzamideand its non-toxic, pharmaceutically acceptable acid addition salts.
 9. Acompound of claim 1 selected from the group consisting of2-[3-(4-methyl-1-piperazinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamideand its non-toxic, pharmaceutically acceptable acid addition salts. 10.A compound of claim 1 selected from the group consisting of2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamideand its non-toxic, pharmaceutically acceptable acid addition salts. 11.A compound of claim 1 selected from the group consisting of2-[2-hydroxy-3-[4-diphenylmethyl)-1-piperazinyl]propoxy]-N-(1-methyl-1H-indol-4-yl)-benzamideand its non-toxic, pharmaceutically acceptable acid addition salts. 12.An antiarrhythmic composition comprising an antiarrythmically effectiveamount of at least one compound of claim 1 and an inert pharmaceuticalcarrier.
 13. A composition of claim 12 wherein R₂ is hydrogen.
 14. Acomposition of claim 13 wherein a and c form a carbon-carbon bond.
 15. Acomposition of claim 12 wherein R₃ is hydrogen.
 16. A composition ofclaim 12 wherein ##STR54## is in the ortho position with respect to B.17. A composition of claim 12 wherein B is --NH--CO-- with NH next tothe indole.
 18. A method of inducing antiarrythmic activity inwarm-blooded animals comprising administering to warm-blooded animals anantiarrythmically effective amount of at least one compound of claim 1.19. A method of claim 18 wherein in the active compound R₃ is hydrogen.20. A method of claim 18 wherein in the active compound ##STR55## is inthe ortho position with respect to B.
 21. A method of claim 18 whereinin the active compound B is --NH--CO-- with NH next to the indole.
 22. Amethod of claim 12 wherein R is hydrogen.
 23. A method of claim 12wherein a and c form a carbon-carbon bond.
 24. A method of claim 12wherein R is hydrogen.
 25. A method of claim 12 wherein ##STR56## is inthe ortho position with respect to b.
 26. A method of claim 12 wherein Bis ##STR57## with NH next to the indole.